You are here

Crowley, Steven Daniel

Overview:

Our laboratory explores the contribution of the immune system and inflammatory mediators to the progression of target organ damage in the setting of cardiovascular disease. We are pursuing several related projects in this field:
(1) The actions of type 1 angiotensin receptors on specific immune cell populations in hypertension, target organ damage, and tissue fibrosis.
(2) Cell-specific actions of inflammatory cytokines in regulating blood pressure and end-organ injury.
(3) Mechanism through which dendritic cells regulate renal sodium reabsorption.
(4) The contributions of Wnt O-acylation to kidney scar formation.

Within the Duke O'Brien Center for Kidney Research (DOCK), I am the director of the Enrichment Core seeking to facilitate training for the broader research community in the skills and strategies used in the study of renal and cardiovascular disease.

I am a leader of the one of the https://medicine.duke.edu/education-and-training/internal-medicine-resid... Academic Societies called the Warren Society that seeks to provide social, service, and research opportunities for a group of residents from the internal medicine training program.

Positions:

Associate Professor of Medicine

Medicine, Nephrology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1996

M.D. — Duke University

News:

Grants:

Role of Dendritic Cell-mediated T Cell Activation in Salt-sensitive Hypertension

Administered By
Medicine, Nephrology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 2016
End Date
March 31, 2020

Role of Th1 Immune Responses in the Pathogenesis of Hypertensive Kidney Injury

Administered By
Medicine, Nephrology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 01, 2010
End Date
February 28, 2019

Role of Drebrin in Vascular Smooth Muscle Remodeling

Administered By
Medicine, Cardiology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
August 20, 2013
End Date
May 31, 2018

Duke Training Grant in Nephrology

Administered By
Medicine, Nephrology
AwardedBy
National Institutes of Health
Role
Preceptor
Start Date
September 20, 1995
End Date
June 30, 2017

Immune Mechanisms in Diabetic Nephropathy

Administered By
Medicine, Nephrology
AwardedBy
Georgia Regents University
Role
Consultant
Start Date
October 01, 2014
End Date
November 30, 2015
Show More

Publications:

The role of macrophages in hypertension and its complications.

Circulating monocytes and tissue macrophages play complex roles in the pathogenesis of hypertension, a highly prevalent disease associated with catastrophic cardiovascular morbidity. In the vasculature and kidney, macrophage-derived reactive oxygen species (ROS) and inflammatory cytokines induce endothelial and epithelial dysfunction, respectively, resulting in vascular oxidative stress and impairment of sodium excretion. By contrast, VEGF-C-expressing macrophages in the skin can facilitate the removal of excess interstitial stores of sodium by stimulating lymphangiogenesis. Inappropriate activation of the renin-angiotensin system (RAS) contributes to essential hypertension in a majority of patients, and macrophages express the type 1 (AT1) receptor for angiotensin II (Ang II). While proinflammatory macrophages clearly contribute to RAS-dependent hypertension, activation of the AT1 receptor directly on macrophages suppresses their M1 polarization and limits tubular and interstitial damage to the kidney during hypertension. Thus, stimulating the macrophage AT1 receptor ameliorates the target organ damage and immune stimulation provoked by AT1 receptor activation in intrinsic renal and vascular cells. The proinflammatory cytokines TNF-α and IL-1β produced by M1 macrophages drive blood pressure elevation and consequent target organ damage. However, additional studies are needed to identify the tissues in which these cytokines act and the signaling pathways they stimulate during hypertension. Moreover, identifying the precise myeloid cell subsets that contribute to hypertension should guide the development of more precise immunomodulatory therapies for patients with persistent blood pressure elevation and progressive end-organ injury.

Authors
Justin Rucker, A; Crowley, SD
MLA Citation
Justin Rucker, A, and Crowley, SD. "The role of macrophages in hypertension and its complications." Pflugers Archiv : European journal of physiology 469.3-4 (April 2017): 419-430.
PMID
28251313
Source
epmc
Published In
Pflügers Archiv
Volume
469
Issue
3-4
Publish Date
2017
Start Page
419
End Page
430
DOI
10.1007/s00424-017-1950-x

The role of chemokines in hypertension and consequent target organ damage.

Immune cells infiltrate the kidney, vasculature, and central nervous system during hypertension, consequently amplifying tissue damage and/or blood pressure elevation. Mononuclear cell motility depends partly on chemokines, which are small cytokines that guide cells through an increasing concentration gradient via ligation of their receptors. Tissue expression of several chemokines is elevated in clinical and experimental hypertension. Likewise, immune cells have enhanced chemokine receptor expression during hypertension, driving immune cell infiltration and inappropriate inflammation in cardiovascular control centers. T lymphocytes and monocytes/macrophages are pivotal mediators of hypertensive inflammation, and these cells migrate in response to several chemokines. As powerful drivers of diapedesis, the chemokines CCL2 and CCL5 have long been implicated in hypertension, but experimental data highlight divergent, context-specific effects of these chemokines on blood pressure and tissue injury. Several other chemokines, particularly those of the CXC family, contribute to blood pressure elevation and target organ damage. Given the significant interplay and chemotactic redundancy among chemokines during disease, future work must not only describe the actions of individual chemokines in hypertension, but also characterize how manipulating a single chemokine modulates the expression and/or function of other chemokines and their cognate receptors. This information will facilitate the design of precise chemotactic immunotherapies to limit cardiovascular and renal morbidity in hypertensive patients.

Authors
Rudemiller, NP; Crowley, SD
MLA Citation
Rudemiller, NP, and Crowley, SD. "The role of chemokines in hypertension and consequent target organ damage." Pharmacological research 119 (March 6, 2017): 404-411.
Website
http://hdl.handle.net/10161/13936
PMID
28279813
Source
epmc
Published In
Pharmacological Research
Volume
119
Publish Date
2017
Start Page
404
End Page
411
DOI
10.1016/j.phrs.2017.02.026

Elevated PTH induces endothelial-to-chondrogenic transition in aortic endothelial cells.

Previous studies have shown that increased parathyroid hormone (PTH) attributable to secondary hyperparathyroidism in chronic kidney disease accelerates the arteriosclerotic fibrosis and calcification. Although the underlying mechanisms remain largely unknown, endothelial cells (ECs) have recently been demonstrated to participate in calcification in part by providing chondrogenic cells via the endothelial-to-mesenchymal transition (EndMT). Therefore, this study aimed to investigate whether elevated PTH could induce endothelial-to-chondrogenic transition in aortic ECs and to determine the possible underlying signaling pathway. We found that treatment of ECs with PTH significantly upregulated the expression of EndMT-related markers. Accordingly, ECs treated with PTH exhibited chondrogenic potential. In vivo, lineage-tracing model-subjected mice with endothelial-specific green fluorescent protein fluorescence to chronic PTH infusion showed a marked increase in the aortic expression of chondrocyte markers, and confocal microscopy revealed the endothelial origin of cells expressing chondrocyte markers in the aorta after PTH infusion. Furthermore, this in vitro study showed that PTH enhanced the nuclear localization of β-catenin in ECs, whereas β-catenin siRNA or DKK1, an inhibitor of β-catenin nuclear translocation, attenuated the upregulation of EndMT-associated and chondrogenic markers induced by PTH. In summary, our study demonstrated that elevated PTH could induce the transition of ECs to chondrogenic cells via EndMT, possibly mediated by the nuclear translocation of β-catenin.

Authors
Wu, M; Zhang, J-D; Tang, R-N; Crowley, SD; Liu, H; Lv, L-L; Ma, K-L; Liu, B-C
MLA Citation
Wu, M, Zhang, J-D, Tang, R-N, Crowley, SD, Liu, H, Lv, L-L, Ma, K-L, and Liu, B-C. "Elevated PTH induces endothelial-to-chondrogenic transition in aortic endothelial cells." American journal of physiology. Renal physiology 312.3 (March 2017): F436-F444.
Website
http://hdl.handle.net/10161/13062
PMID
27582099
Source
epmc
Published In
American Journal of Physiology: Renal Physiology
Volume
312
Issue
3
Publish Date
2017
Start Page
F436
End Page
F444
DOI
10.1152/ajprenal.00210.2016

Immunologic Effects of the Renin-Angiotensin System.

Inappropriate activation of the renin-angiotensin system (RAS) exacerbates renal and vascular injury. Accordingly, treatment with global RAS antagonists attenuates cardiovascular risk and slows the progression of proteinuric kidney disease. By reducing BP, RAS inhibitors limit secondary immune activation responding to hemodynamic injury in the target organ. However, RAS activation in hematopoietic cells has immunologic effects that diverge from those of RAS stimulation in the kidney and vasculature. In preclinical studies, activating type 1 angiotensin (AT1) receptors in T lymphocytes and myeloid cells blunts the polarization of these cells toward proinflammatory phenotypes, protecting the kidney from hypertensive injury and fibrosis. These endogenous functions of immune AT1 receptors temper the pathogenic actions of renal and vascular AT1 receptors during hypertension. By counteracting the effects of AT1 receptor stimulation in the target organ, exogenous administration of AT2 receptor agonists or angiotensin 1-7 analogs may similarly limit inflammatory injury to the heart and kidney. Moreover, although angiotensin II is the classic effector molecule of the RAS, several RAS enzymes affect immune homeostasis independently of canonic angiotensin II generation. Thus, as reviewed here, multiple components of the RAS signaling cascade influence inflammatory cell phenotype and function with unpredictable and context-specific effects on innate and adaptive immunity.

Authors
Crowley, SD; Rudemiller, NP
MLA Citation
Crowley, SD, and Rudemiller, NP. "Immunologic Effects of the Renin-Angiotensin System." Journal of the American Society of Nephrology : JASN (February 2017).
Website
http://hdl.handle.net/10161/13735
PMID
28151411
Source
epmc
Published In
Journal of the American Society of Nephrology : JASN
Publish Date
2017
DOI
10.1681/asn.2016101066

Targeting cytokine signaling in salt-sensitive hypertension.

Activated immune cell populations contribute to hypertension in part through inciting damage to the kidney and by provoking inappropriate sodium reabsorption in the nephron. Inflammatory mediators called cytokines produced by T lymphocytes and macrophages act on specific sodium transporters in the kidney, augmenting their activity or expression, with consequent expansion of intravascular fluid volume and cardiac output. The overlapping functions of these cytokines, each of which may activate multiple receptors, present challenges in precisely targeting inflammatory signaling cascades in hypertension. Moreover, broad immune suppression could expose the hypertensive patient to disproportional risks of infection or malignancy. Nevertheless, the possibility that incisive immunomodulatory therapies could provide cardiovascular and renal protection through both blood pressure-dependent and -independent mechanisms justifies comprehensive investigation into the relevant signaling pathways and tissue sites in which inflammatory cytokines function to exaggerate blood pressure elevation and target organ damage in hypertension.

Authors
Crowley, SD; Jeffs, AD
MLA Citation
Crowley, SD, and Jeffs, AD. "Targeting cytokine signaling in salt-sensitive hypertension." American journal of physiology. Renal physiology 311.6 (December 2016): F1153-F1158.
Website
http://hdl.handle.net/10161/13063
PMID
27558557
Source
epmc
Published In
American Journal of Physiology: Renal Physiology
Volume
311
Issue
6
Publish Date
2016
Start Page
F1153
End Page
F1158
DOI
10.1152/ajprenal.00273.2016

C-C Motif Chemokine 5 Attenuates Angiotensin II-Dependent Kidney Injury by Limiting Renal Macrophage Infiltration.

Inappropriate activation of the renin angiotensin system (RAS) is a key contributor to the pathogenesis of essential hypertension. During RAS activation, infiltration of immune cells into the kidney exacerbates hypertension and renal injury. However, the mechanisms underpinning the accumulation of mononuclear cells in the kidney after RAS stimulation remain unclear. C-C motif chemokine 5 (CCL5) drives recruitment of macrophages and T lymphocytes into injured tissues, and we have found that RAS activation induces CCL5 expression in the kidney during the pathogenesis of hypertension and renal fibrosis. We therefore evaluated the contribution of CCL5 to renal damage and fibrosis in hypertensive and normotensive models of RAS stimulation. Surprisingly, during angiotensin II-induced hypertension, CCL5-deficient (knockout, KO) mice exhibited markedly augmented kidney damage, macrophage infiltration, and expression of proinflammatory macrophage cytokines compared with wild-type controls. When subjected to the normotensive unilateral ureteral obstruction model of endogenous RAS activation, CCL5 KO mice similarly developed more severe renal fibrosis and greater accumulation of macrophages in the kidney, congruent with enhanced renal expression of the macrophage chemokine CCL2. In turn, pharmacologic inhibition of CCL2 abrogated the differences between CCL5 KO and wild-type mice in kidney fibrosis and macrophage infiltration after unilateral ureteral obstruction. These data indicate that CCL5 paradoxically limits macrophage accumulation in the injured kidney during RAS activation by constraining the proinflammatory actions of CCL2.

Authors
Rudemiller, NP; Patel, MB; Zhang, J-D; Jeffs, AD; Karlovich, NS; Griffiths, R; Kan, MJ; Buckley, AF; Gunn, MD; Crowley, SD
MLA Citation
Rudemiller, NP, Patel, MB, Zhang, J-D, Jeffs, AD, Karlovich, NS, Griffiths, R, Kan, MJ, Buckley, AF, Gunn, MD, and Crowley, SD. "C-C Motif Chemokine 5 Attenuates Angiotensin II-Dependent Kidney Injury by Limiting Renal Macrophage Infiltration." The American journal of pathology 186.11 (November 2016): 2846-2856.
Website
http://hdl.handle.net/10161/13061
PMID
27640148
Source
epmc
Published In
The American journal of pathology
Volume
186
Issue
11
Publish Date
2016
Start Page
2846
End Page
2856
DOI
10.1016/j.ajpath.2016.07.015

Competing Actions of Type 1 Angiotensin II Receptors Expressed on T Lymphocytes and Kidney Epithelium during Cisplatin-Induced AKI.

Inappropriate activation of the renin-angiotensin system (RAS) contributes to many CKDs. However, the role of the RAS in modulating AKI requires elucidation, particularly because stimulating type 1 angiotensin II (AT1) receptors in the kidney or circulating inflammatory cells can have opposing effects on the generation of inflammatory mediators that underpin the pathogenesis of AKI. For example, TNF-α is a fundamental driver of cisplatin nephrotoxicity, and generation of TNF-α is suppressed or enhanced by AT1 receptor signaling in T lymphocytes or the distal nephron, respectively. In this study, cell tracking experiments with CD4-Cre mT/mG reporter mice revealed robust infiltration of T lymphocytes into the kidney after cisplatin injection. Notably, knockout of AT1 receptors on T lymphocytes exacerbated the severity of cisplatin-induced AKI and enhanced the cisplatin-induced increase in TNF-α levels locally within the kidney and in the systemic circulation. In contrast, knockout of AT1 receptors on kidney epithelial cells ameliorated the severity of AKI and suppressed local and systemic TNF-α production induced by cisplatin. Finally, disrupting TNF-α production specifically within the renal tubular epithelium attenuated the AKI and the increase in circulating TNF-α levels induced by cisplatin. These results illustrate discrepant tissue-specific effects of RAS stimulation on cisplatin nephrotoxicity and raise the concern that inflammatory mediators produced by renal parenchymal cells may influence the function of remote organs by altering systemic cytokine levels. Our findings suggest selective inhibition of AT1 receptors within the nephron as a promising intervention for protecting patients from cisplatin-induced nephrotoxicity.

Authors
Zhang, J; Rudemiller, NP; Patel, MB; Wei, Q; Karlovich, NS; Jeffs, AD; Wu, M; Sparks, MA; Privratsky, JR; Herrera, M; Gurley, SB; Nedospasov, SA; Crowley, SD
MLA Citation
Zhang, J, Rudemiller, NP, Patel, MB, Wei, Q, Karlovich, NS, Jeffs, AD, Wu, M, Sparks, MA, Privratsky, JR, Herrera, M, Gurley, SB, Nedospasov, SA, and Crowley, SD. "Competing Actions of Type 1 Angiotensin II Receptors Expressed on T Lymphocytes and Kidney Epithelium during Cisplatin-Induced AKI." Journal of the American Society of Nephrology : JASN 27.8 (August 2016): 2257-2264.
Website
http://hdl.handle.net/10161/11963
PMID
26744488
Source
epmc
Published In
Journal of the American Society of Nephrology : JASN
Volume
27
Issue
8
Publish Date
2016
Start Page
2257
End Page
2264
DOI
10.1681/asn.2015060683

Interactions Between the Immune and the Renin-Angiotensin Systems in Hypertension.

Authors
Rudemiller, NP; Crowley, SD
MLA Citation
Rudemiller, NP, and Crowley, SD. "Interactions Between the Immune and the Renin-Angiotensin Systems in Hypertension." Hypertension (Dallas, Tex. : 1979) 68.2 (August 2016): 289-296.
Website
http://hdl.handle.net/10161/12534
PMID
27354427
Source
epmc
Published In
Hypertension
Volume
68
Issue
2
Publish Date
2016
Start Page
289
End Page
296
DOI
10.1161/hypertensionaha.116.06591

Experimental inhibition of porcupine-mediated Wnt O-acylation attenuates kidney fibrosis.

Activated Wnt signaling is critical in the pathogenesis of renal fibrosis, a final common pathway for most forms of chronic kidney disease. Therapeutic intervention by inhibition of individual Wnts or downstream Wnt/β-catenin signaling has been proposed, but these approaches do not interrupt the functions of all Wnts nor block non-canonical Wnt signaling pathways. Alternatively, an orally bioavailable small molecule, Wnt-C59, blocks the catalytic activity of the Wnt-acyl transferase porcupine, and thereby prevents secretion of all Wnt isoforms. We found that inhibiting porcupine dramatically attenuates kidney fibrosis in the murine unilateral ureteral obstruction model. Wnt-C59 treatment similarly blunts collagen mRNA expression in the obstructed kidney. Consistent with its actions to broadly arrest Wnt signaling, porcupine inhibition reduces expression of Wnt target genes and bolsters nuclear exclusion of β-catenin in the kidney following ureteral obstruction. Importantly, prevention of Wnt secretion by Wnt-C59 blunts expression of inflammatory cytokines in the obstructed kidney that otherwise provoke a positive feedback loop of Wnt expression in collagen-producing fibroblasts and epithelial cells. Thus, therapeutic targeting of porcupine abrogates kidney fibrosis not only by overcoming the redundancy of individual Wnt isoforms but also by preventing upstream cytokine-induced Wnt generation. These findings reveal a novel therapeutic maneuver to protect the kidney from fibrosis by interrupting a pathogenic crosstalk loop between locally generated inflammatory cytokines and the Wnt/β-catenin signaling pathway.

Authors
Madan, B; Patel, MB; Zhang, J; Bunte, RM; Rudemiller, NP; Griffiths, R; Virshup, DM; Crowley, SD
MLA Citation
Madan, B, Patel, MB, Zhang, J, Bunte, RM, Rudemiller, NP, Griffiths, R, Virshup, DM, and Crowley, SD. "Experimental inhibition of porcupine-mediated Wnt O-acylation attenuates kidney fibrosis." Kidney international 89.5 (May 2016): 1062-1074.
Website
http://hdl.handle.net/10161/11962
PMID
27083283
Source
epmc
Published In
Kidney international
Volume
89
Issue
5
Publish Date
2016
Start Page
1062
End Page
1074
DOI
10.1016/j.kint.2016.01.017

Interleukin-1 Receptor Activation Potentiates Salt Reabsorption in Angiotensin II-Induced Hypertension via the NKCC2 Co-transporter in the Nephron.

Hypertension is among the most prevalent and catastrophic chronic diseases worldwide. While the efficacy of renin angiotensin system (RAS) blockade in lowering blood pressure illustrates that the RAS is broadly activated in human hypertension, the frequent failure of RAS inhibition to prevent or reverse hypertensive organ damage highlights the need for novel therapies to combat RAS-dependent hypertension. We previously discovered elevated levels of the macrophage cytokine IL-1 in the kidney in a murine model of RAS-mediated hypertension. Here we report that IL-1 receptor (IL-1R1) deficiency or blockade limits blood pressure elevation in this model by mitigating sodium reabsorption via the NKCC2 co-transporter in the nephron. In this setting, IL-1R1 activation prevents intra-renal myeloid cells from maturing into Ly6C(+)Ly6G(-) macrophages that elaborate nitric oxide, a natriuretic hormone that suppresses NKCC2 activity. By revealing how the innate immune system regulates tubular sodium transport, these experiments should lead to new immunomodulatory anti-hypertensive therapies.

Authors
Zhang, J; Rudemiller, NP; Patel, MB; Karlovich, NS; Wu, M; McDonough, AA; Griffiths, R; Sparks, MA; Jeffs, AD; Crowley, SD
MLA Citation
Zhang, J, Rudemiller, NP, Patel, MB, Karlovich, NS, Wu, M, McDonough, AA, Griffiths, R, Sparks, MA, Jeffs, AD, and Crowley, SD. "Interleukin-1 Receptor Activation Potentiates Salt Reabsorption in Angiotensin II-Induced Hypertension via the NKCC2 Co-transporter in the Nephron." Cell metabolism 23.2 (February 2016): 360-368.
PMID
26712462
Source
epmc
Published In
Cell Metabolism
Volume
23
Issue
2
Publish Date
2016
Start Page
360
End Page
368
DOI
10.1016/j.cmet.2015.11.013

Megalin/Cubulin-Lysosome-mediated Albumin Reabsorption Is Involved in the Tubular Cell Activation of NLRP3 Inflammasome and Tubulointerstitial Inflammation.

Albuminuria contributes to the development and progression of chronic kidney disease by inducing tubulointerstitial inflammation (TI) and fibrosis. However, the exact mechanisms of TI in response to albuminuria are unresolved. We previously demonstrated that NLRP3 and inflammasomes mediate albumin-induced lesions in tubular cells. Here, we further investigated the role of endocytic receptors and lysosome rupture in NLRP3 inflammasome activation. A murine proteinuric nephropathy model was induced by albumin overload as described previously. The priming and activation signals for inflammasome complex formation were evoked simultaneously by albumin excess in tubular epithelial cells. The former signal was dependent on a albumin-triggered NF-κB pathway activation. This process is mediated by the endocytic receptor, megalin and cubilin. However, the silencing of megalin or cubilin inhibited the albumin-induced NLRP3 signal. Notably, subsequent lysosome rupture and the corresponding release of lysosomal hydrolases, especially cathepsin B, were observed in tubular epithelial cells exposed to albumin. Cathepsin B release and distribution are essential for NLRP3 signal activation, and inhibitors of cathepsin B suppressed the NLRP3 signal in tubular epithelial cells. Taken together, our findings suggest that megalin/cubilin and lysosome rupture are involved in albumin-triggered tubular injury and TI. This study provides novel insights into albuminuria-induced TI and implicates the active control of albuminuria as a critical strategy to halt the progression of chronic kidney disease.

Authors
Liu, D; Wen, Y; Tang, T-T; Lv, L-L; Tang, R-N; Liu, H; Ma, K-L; Crowley, SD; Liu, B-C
MLA Citation
Liu, D, Wen, Y, Tang, T-T, Lv, L-L, Tang, R-N, Liu, H, Ma, K-L, Crowley, SD, and Liu, B-C. "Megalin/Cubulin-Lysosome-mediated Albumin Reabsorption Is Involved in the Tubular Cell Activation of NLRP3 Inflammasome and Tubulointerstitial Inflammation." The Journal of biological chemistry 290.29 (July 2015): 18018-18028.
PMID
26025362
Source
epmc
Published In
The Journal of biological chemistry
Volume
290
Issue
29
Publish Date
2015
Start Page
18018
End Page
18028
DOI
10.1074/jbc.m115.662064

Role of T lymphocytes in hypertension.

Accumulating evidence indicates that the immune system plays a critical role in the pathogenesis of cardiovascular diseases including hypertension. Mice lacking T lymphocytes are resistant to blood pressure elevation, suggesting a key contribution of T lymphocytes to hypertension. However, the individual T cell subsets, including CD8(+), Th1, Th17, and T regulatory T cells have shown widely discrepant effects on blood pressure and target organ damage in this disorder. Moreover, the activation state of a T lymphocyte population exerts considerable influence over its role in hypertension. In turn, activated T cells regulate blood pressure through the elaboration of reactive oxygen species and vasoactive cytokines, altering the inflammatory milieu in the vascular wall and the kidney. Recent GWAS studies similarly point to a role for T lymphocytes in human hypertension.

Authors
Zhang, J; Crowley, SD
MLA Citation
Zhang, J, and Crowley, SD. "Role of T lymphocytes in hypertension." Current opinion in pharmacology 21 (April 2015): 14-19. (Review)
PMID
25523165
Source
epmc
Published In
Current Opinion in Pharmacology
Volume
21
Publish Date
2015
Start Page
14
End Page
19
DOI
10.1016/j.coph.2014.12.003

Tumor necrosis factor-α produced in the kidney contributes to angiotensin II-dependent hypertension.

Immune system activation contributes to the pathogenesis of hypertension and the resulting progression of chronic kidney disease. In this regard, we recently identified a role for proinflammatory Th1 T-lymphocyte responses in hypertensive kidney injury. Because Th1 cells generate interferon-γ and tumor necrosis factor-α (TNF-α), we hypothesized that interferon-γ and TNF-α propagate renal damage during hypertension induced by activation of the renin-angiotensin system. Therefore, after confirming that mice genetically deficient of Th1 immunity were protected from kidney glomerular injury despite a preserved hypertensive response, we subjected mice lacking interferon-γ or TNF-α to our model of hypertensive chronic kidney disease. Interferon deficiency had no impact on blood pressure elevation or urinary albumin excretion during chronic angiotensin II infusion. By contrast, TNF-deficient (knockout) mice had blunted hypertensive responses and reduced end-organ damage in our model. As angiotensin II-infused TNF knockout mice had exaggerated endothelial nitric oxide synthase expression in the kidney and enhanced nitric oxide bioavailability, we examined the actions of TNF-α generated from renal parenchymal cells in hypertension by transplanting wild-type or TNF knockout kidneys into wild-type recipients before the induction of hypertension. Transplant recipients lacking TNF solely in the kidney had blunted hypertensive responses to angiotensin II and augmented renal endothelial nitric oxide synthase expression, confirming a role for kidney-derived TNF-α to promote angiotensin II-induced blood pressure elevation by limiting renal nitric oxide generation.

Authors
Zhang, J; Patel, MB; Griffiths, R; Mao, A; Song, Y-S; Karlovich, NS; Sparks, MA; Jin, H; Wu, M; Lin, EE; Crowley, SD
MLA Citation
Zhang, J, Patel, MB, Griffiths, R, Mao, A, Song, Y-S, Karlovich, NS, Sparks, MA, Jin, H, Wu, M, Lin, EE, and Crowley, SD. "Tumor necrosis factor-α produced in the kidney contributes to angiotensin II-dependent hypertension." Hypertension (Dallas, Tex. : 1979) 64.6 (December 2014): 1275-1281.
PMID
25185128
Source
epmc
Published In
Hypertension
Volume
64
Issue
6
Publish Date
2014
Start Page
1275
End Page
1281
DOI
10.1161/hypertensionaha.114.03863

Activation of the Nlrp3 inflammasome by mitochondrial reactive oxygen species: a novel mechanism of albumin-induced tubulointerstitial inflammation.

Albuminuria is not only an important marker of chronic kidney disease but also a crucial contributor to tubulointerstitial inflammation (TIF). In this study, we determined whether activation of the Nlrp3 inflammasome is involved in albuminuria induced-TIF and the underlying mechanisms of inflammasome activation by mitochondrial reactive oxygen species (mROS). We established an albumin-overload induced rat nephropathy model characterised by albuminuria, renal infiltration of inflammatory cells, tubular dilation and atrophy. The renal expression levels of the Nlrp3 inflammasome, IL-1β and IL-18 were significantly increased in this animal model. In vitro, albumin time- and dose-dependently increased the expression levels of the Nlrp3 inflammasome, IL-1β and IL18. Moreover, the silencing of the Nlrp3 gene or the use of the caspase-1 inhibitor Z-VAD-fmk significantly attenuated the albumin-induced increase in IL-1β and IL-18 expression in HK2 cells. In addition, mROS generation was elevated by albumin stimulation, whereas the ROS scavenger N-acetyl-l-cysteine (NAC) inhibited Nlrp3 expression and the release of IL-1β and IL-18. In kidney biopsy specimens obtained from patients with IgA nephropathy, Nlrp3 expression was localised to the proximal tubular epithelial cells, and this result is closely correlated with the extent of proteinuria and TIF. In summary, this study demonstrates that albuminuria may serve as an endogenous danger-associated molecular pattern (DAMP) that stimulates TIF via the mROS-mediated activation of the cytoplasmic Nlrp3 inflammasome.

Authors
Liu, D; Xu, M; Ding, L-H; Lv, L-L; Liu, H; Ma, K-L; Zhang, A-H; Crowley, SD; Liu, B-C
MLA Citation
Liu, D, Xu, M, Ding, L-H, Lv, L-L, Liu, H, Ma, K-L, Zhang, A-H, Crowley, SD, and Liu, B-C. "Activation of the Nlrp3 inflammasome by mitochondrial reactive oxygen species: a novel mechanism of albumin-induced tubulointerstitial inflammation." The international journal of biochemistry & cell biology 57 (December 2014): 7-19.
PMID
25281528
Source
epmc
Published In
The International Journal of Biochemistry & Cell Biology
Volume
57
Publish Date
2014
Start Page
7
End Page
19
DOI
10.1016/j.biocel.2014.09.018

Linking angiotensin II to nuclear factor-κ light chain enhancer of activated B cells-induced cardiovascular damage: bad CARMAs.

Authors
Crowley, SD
MLA Citation
Crowley, SD. "Linking angiotensin II to nuclear factor-κ light chain enhancer of activated B cells-induced cardiovascular damage: bad CARMAs." Hypertension (Dallas, Tex. : 1979) 64.5 (November 2014): 933-934.
PMID
25185129
Source
epmc
Published In
Hypertension
Volume
64
Issue
5
Publish Date
2014
Start Page
933
End Page
934
DOI
10.1161/hypertensionaha.114.04047

Endothelial Cell Autoantibodies in Predicting Declining Renal Function, End-Stage Renal Disease, or Death in Adult Type 2 Diabetic Nephropathy

Authors
Zimering, MB; Zhang, JH; Guarino, PD; Emanuele, N; McCullough, PA; Fried, LF
MLA Citation
Zimering, MB, Zhang, JH, Guarino, PD, Emanuele, N, McCullough, PA, and Fried, LF. "Endothelial Cell Autoantibodies in Predicting Declining Renal Function, End-Stage Renal Disease, or Death in Adult Type 2 Diabetic Nephropathy." Frontiers in Endocrinology 5 (August 11, 2014).
Source
crossref
Published In
Frontiers in Endocrinology
Volume
5
Publish Date
2014
DOI
10.3389/fendo.2014.00128

Classical Renin-Angiotensin system in kidney physiology.

The renin-angiotensin system has powerful effects in control of the blood pressure and sodium homeostasis. These actions are coordinated through integrated actions in the kidney, cardiovascular system and the central nervous system. Along with its impact on blood pressure, the renin-angiotensin system also influences a range of processes from inflammation and immune responses to longevity. Here, we review the actions of the "classical" renin-angiotensin system, whereby the substrate protein angiotensinogen is processed in a two-step reaction by renin and angiotensin converting enzyme, resulting in the sequential generation of angiotensin I and angiotensin II, the major biologically active renin-angiotensin system peptide, which exerts its actions via type 1 and type 2 angiotensin receptors. In recent years, several new enzymes, peptides, and receptors related to the renin-angiotensin system have been identified, manifesting a complexity that was previously unappreciated. While the functions of these alternative pathways will be reviewed elsewhere in this journal, our focus here is on the physiological role of components of the "classical" renin-angiotensin system, with an emphasis on new developments and modern concepts.

Authors
Sparks, MA; Crowley, SD; Gurley, SB; Mirotsou, M; Coffman, TM
MLA Citation
Sparks, MA, Crowley, SD, Gurley, SB, Mirotsou, M, and Coffman, TM. "Classical Renin-Angiotensin system in kidney physiology." Comprehensive Physiology 4.3 (July 2014): 1201-1228. (Review)
PMID
24944035
Source
epmc
Published In
Comprehensive Physiology
Volume
4
Issue
3
Publish Date
2014
Start Page
1201
End Page
1228
DOI
10.1002/cphy.c130040

The inextricable role of the kidney in hypertension.

An essential link between the kidney and blood pressure control has long been known. Here, we review evidence supporting the premise that an impaired capacity of the kidney to excrete sodium in response to elevated blood pressure is a major contributor to hypertension, irrespective of the initiating cause. In this regard, recent work suggests that novel pathways controlling key sodium transporters in kidney epithelia have a critical impact on hypertension pathogenesis, supporting a model in which impaired renal sodium excretion is a final common pathway through which vascular, neural, and inflammatory responses raise blood pressure. We also address recent findings calling into question long-standing notions regarding the relationship between sodium intake and changes in body fluid volume. Expanded understanding of the role of the kidney as both a cause and target of hypertension highlights key aspects of pathophysiology and may lead to identification of new strategies for prevention and treatment.

Authors
Coffman, TM
MLA Citation
Coffman, TM. "The inextricable role of the kidney in hypertension." The Journal of clinical investigation 124.6 (June 2, 2014): 2341-2347. (Review)
PMID
24892708
Source
epmc
Published In
Journal of Clinical Investigation
Volume
124
Issue
6
Publish Date
2014
Start Page
2341
End Page
2347
DOI
10.1172/jci72274

Type 1 angiotensin receptors on macrophages ameliorate IL-1 receptor-mediated kidney fibrosis.

In a wide array of kidney diseases, type 1 angiotensin (AT1) receptors are present on the immune cells that infiltrate the renal interstitium. Here, we examined the actions of AT1 receptors on macrophages in progressive renal fibrosis and found that macrophage-specific AT1 receptor deficiency exacerbates kidney fibrosis induced by unilateral ureteral obstruction (UUO). Macrophages isolated from obstructed kidneys of mice lacking AT1 receptors solely on macrophages had heightened expression of proinflammatory M1 cytokines, including IL-1. Evaluation of isolated AT1 receptor-deficient macrophages confirmed the propensity of these cells to produce exaggerated levels of M1 cytokines, which led to more severe renal epithelial cell damage via IL-1 receptor activation in coculture compared with WT macrophages. A murine kidney crosstransplantation concomitant with UUO model revealed that augmentation of renal fibrosis instigated by AT1 receptor-deficient macrophages is mediated by IL-1 receptor stimulation in the kidney. This study indicates that a key role of AT1 receptors on macrophages is to protect the kidney from fibrosis by limiting activation of IL-1 receptors in the kidney.

Authors
Zhang, J-D; Patel, MB; Griffiths, R; Dolber, PC; Ruiz, P; Sparks, MA; Stegbauer, J; Jin, H; Gomez, JA; Buckley, AF; Lefler, WS; Chen, D; Crowley, SD
MLA Citation
Zhang, J-D, Patel, MB, Griffiths, R, Dolber, PC, Ruiz, P, Sparks, MA, Stegbauer, J, Jin, H, Gomez, JA, Buckley, AF, Lefler, WS, Chen, D, and Crowley, SD. "Type 1 angiotensin receptors on macrophages ameliorate IL-1 receptor-mediated kidney fibrosis." The Journal of clinical investigation 124.5 (May 2014): 2198-2203.
PMID
24743144
Source
epmc
Published In
Journal of Clinical Investigation
Volume
124
Issue
5
Publish Date
2014
Start Page
2198
End Page
2203
DOI
10.1172/jci61368

Cinacalcet ameliorates cardiac fibrosis in uremic hearts through suppression of endothelial-to-mesenchymal transition.

Authors
Wu, M; Tang, R-N; Liu, H; Pan, M-M; Lv, L-L; Zhang, J-D; Crowley, SD; Liu, B-C
MLA Citation
Wu, M, Tang, R-N, Liu, H, Pan, M-M, Lv, L-L, Zhang, J-D, Crowley, SD, and Liu, B-C. "Cinacalcet ameliorates cardiac fibrosis in uremic hearts through suppression of endothelial-to-mesenchymal transition." Int J Cardiol 171.3 (February 15, 2014): e65-e69. (Letter)
PMID
24382406
Source
pubmed
Published In
International Journal of Cardiology
Volume
171
Issue
3
Publish Date
2014
Start Page
e65
End Page
e69
DOI
10.1016/j.ijcard.2013.11.105

Cinacalcet ameliorates cardiac fibrosis in uremic hearts through suppression of endothelial-to-mesenchymal transition

Authors
Wu, M; Tang, RN; Liu, H; Pan, MM; Lv, LL; Zhang, JD; Crowley, SD; Liu, BC
MLA Citation
Wu, M, Tang, RN, Liu, H, Pan, MM, Lv, LL, Zhang, JD, Crowley, SD, and Liu, BC. "Cinacalcet ameliorates cardiac fibrosis in uremic hearts through suppression of endothelial-to-mesenchymal transition." International Journal of Cardiology 171.3 (February 15, 2014). (Letter)
Source
scopus
Published In
International Journal of Cardiology
Volume
171
Issue
3
Publish Date
2014
DOI
10.1016/j.ijcard.2013.11.105

The cooperative roles of inflammation and oxidative stress in the pathogenesis of hypertension.

SIGNIFICANCE: Innate and adaptive immunity play fundamental roles in the development of hypertension and its complications. As effectors of the cell-mediated immune response, myeloid cells and T lymphocytes protect the host organism from infection by attacking foreign intruders with bursts of reactive oxygen species (ROS). RECENT ADVANCES: While these ROS may help to preserve the vascular tone and thereby protect against circulatory collapse in the face of overwhelming infection, aberrant elaboration of ROS triggered by immune cells in the absence of a hemodynamic insult can lead to pathologic increases in blood pressure. Conversely, misdirected oxidative stress in cardiovascular control organs, including the vasculature, the kidney, and the nervous system potentiates inflammatory responses, augmenting blood pressure elevation and inciting target organ damage. CRITICAL ISSUES: Inflammation and oxidative stress thereby act as cooperative and synergistic partners in the pathogenesis of hypertension. FUTURE DIRECTIONS: Pharmacologic interventions for hypertensive patients will need to exploit this robust bidirectional relationship between ROS generation and immune activation in cardiovascular control organs to maximize therapeutic benefit, while limiting off-target side effects.

Authors
Crowley, SD
MLA Citation
Crowley, SD. "The cooperative roles of inflammation and oxidative stress in the pathogenesis of hypertension." Antioxid Redox Signal 20.1 (January 1, 2014): 102-120. (Review)
PMID
23472597
Source
pubmed
Published In
Antioxidants & Redox Signaling
Volume
20
Issue
1
Publish Date
2014
Start Page
102
End Page
120
DOI
10.1089/ars.2013.5258

Staphylococcus aureus sepsis induces early renal mitochondrial DNA repair and mitochondrial biogenesis in mice.

Acute kidney injury (AKI) contributes to the high morbidity and mortality of multi-system organ failure in sepsis. However, recovery of renal function after sepsis-induced AKI suggests active repair of energy-producing pathways. Here, we tested the hypothesis in mice that Staphyloccocus aureus sepsis damages mitochondrial DNA (mtDNA) in the kidney and activates mtDNA repair and mitochondrial biogenesis. Sepsis was induced in wild-type C57Bl/6J and Cox-8 Gfp-tagged mitochondrial-reporter mice via intraperitoneal fibrin clots embedded with S. aureus. Kidneys from surviving mice were harvested at time zero (control), 24, or 48 hours after infection and evaluated for renal inflammation, oxidative stress markers, mtDNA content, and mitochondrial biogenesis markers, and OGG1 and UDG mitochondrial DNA repair enzymes. We examined the kidneys of the mitochondrial reporter mice for changes in staining density and distribution. S. aureus sepsis induced sharp amplification of renal Tnf, Il-10, and Ngal mRNAs with decreased renal mtDNA content and increased tubular and glomerular cell death and accumulation of protein carbonyls and 8-OHdG. Subsequently, mtDNA repair and mitochondrial biogenesis was evidenced by elevated OGG1 levels and significant increases in NRF-1, NRF-2, and mtTFA expression. Overall, renal mitochondrial mass, tracked by citrate synthase mRNA and protein, increased in parallel with changes in mitochondrial GFP-fluorescence especially in proximal tubules in the renal cortex and medulla. Sub-lethal S. aureus sepsis thus induces widespread renal mitochondrial damage that triggers the induction of the renal mtDNA repair protein, OGG1, and mitochondrial biogenesis as a conspicuous resolution mechanism after systemic bacterial infection.

Authors
Bartz, RR; Fu, P; Suliman, HB; Crowley, SD; MacGarvey, NC; Welty-Wolf, K; Piantadosi, CA
MLA Citation
Bartz, RR, Fu, P, Suliman, HB, Crowley, SD, MacGarvey, NC, Welty-Wolf, K, and Piantadosi, CA. "Staphylococcus aureus sepsis induces early renal mitochondrial DNA repair and mitochondrial biogenesis in mice." PloS one 9.7 (January 2014): e100912-.
PMID
24988481
Source
epmc
Published In
PloS one
Volume
9
Issue
7
Publish Date
2014
Start Page
e100912
DOI
10.1371/journal.pone.0100912

Linking angiotensin II to nuclear factor-κ light chain enhancer of activated B cells-induced cardiovascular damage: Bad carmas

Authors
Crowley, SD
MLA Citation
Crowley, SD. "Linking angiotensin II to nuclear factor-κ light chain enhancer of activated B cells-induced cardiovascular damage: Bad carmas." Hypertension (2014).
Source
scival
Published In
Hypertension
Publish Date
2014
DOI
10.1161/HYPERTENSIONAHA.114.04047

Tumor necrosis factor-α produced in the kidney contributes to angiotensin II-dependent hypertension

Immune system activation contributes to the pathogenesis of hypertension and the resulting progression of chronic kidney disease. In this regard, we recently identified a role for proinflammatory Th1 T-lymphocyte responses in hypertensive kidney injury. Because Th1 cells generate interferon-γ and tumor necrosis factor-α (TNF-α), we hypothesized that interferon-γ and TNF-α propagate renal damage during hypertension induced by activation of the renin-angiotensin system. Therefore, after confirming that mice genetically deficient of Th1 immunity were protected from kidney glomerular injury despite a preserved hypertensive response, we subjected mice lacking interferon-γ or TNF-α to our model of hypertensive chronic kidney disease. Interferon deficiency had no impact on blood pressure elevation or urinary albumin excretion during chronic angiotensin II infusion. By contrast, TNF-deficient (knockout) mice had blunted hypertensive responses and reduced end-organ damage in our model. As angiotensin II-infused TNF knockout mice had exaggerated endothelial nitric oxide synthase expression in the kidney and enhanced nitric oxide bioavailability, we examined the actions of TNF-α generated from renal parenchymal cells in hypertension by transplanting wild-type or TNF knockout kidneys into wild-type recipients before the induction of hypertension. Transplant recipients lacking TNF solely in the kidney had blunted hypertensive responses to angiotensin II and augmented renal endothelial nitric oxide synthase expression, confirming a role for kidney-derived TNF-α to promote angiotensin II-induced blood pressure elevation by limiting renal nitric oxide generation.

Authors
Zhang, J; Patel, MB; Griffiths, R; Mao, A; Song, Y-S; Karlovich, NS; Sparks, MA; Jin, H; Wu, M; Lin, EE; Crowley, SD
MLA Citation
Zhang, J, Patel, MB, Griffiths, R, Mao, A, Song, Y-S, Karlovich, NS, Sparks, MA, Jin, H, Wu, M, Lin, EE, and Crowley, SD. "Tumor necrosis factor-α produced in the kidney contributes to angiotensin II-dependent hypertension." Hypertension (2014).
Source
scival
Published In
Hypertension
Publish Date
2014
DOI
10.1161/HYPERTENSIONAHA.114.03863

The role of type 1 angiotensin receptors on T lymphocytes in cardiovascular and renal diseases.

The renin-angiotensin system plays a critical role in the pathogenesis of several cardiovascular diseases, largely through activation of type I angiotensin (AT(1)) receptors by angiotensin II. Treatment with AT(1) receptor blockers (ARBs) is a proven successful intervention for hypertension and progressive heart and kidney disease. However, the divergent actions of AT(1) receptors on individual cell lineages in hypertension may present novel opportunities to optimize the therapeutic benefits of ARBs. For example, T lymphocytes make important contributions to the induction and progression of various cardiovascular diseases, but new experiments indicate that activation of AT(1) receptors on T cells paradoxically limits inflammation and target organ damage in hypertension. Future studies should illustrate how these discrepant functions of AT(1) receptors in target organs versus mononuclear cells can be exploited for the benefit of patients with recalcitrant hypertension and other cardiovascular diseases.

Authors
Zhang, J; Crowley, SD
MLA Citation
Zhang, J, and Crowley, SD. "The role of type 1 angiotensin receptors on T lymphocytes in cardiovascular and renal diseases." Curr Hypertens Rep 15.1 (February 2013): 39-46.
PMID
23160867
Source
pubmed
Published In
Current Hypertension Reports
Volume
15
Issue
1
Publish Date
2013
Start Page
39
End Page
46
DOI
10.1007/s11906-012-0318-z

The role of type 1 angiotensin receptors on t lymphocytes in cardiovascular and renal diseases

The renin-angiotensin system plays a critical role in the pathogenesis of several cardiovascular diseases, largely through activation of type I angiotensin (AT1) receptors by angiotensin II. Treatment with AT 1 receptor blockers (ARBs) is a proven successful intervention for hypertension and progressive heart and kidney disease. However, the divergent actions of AT1 receptors on individual cell lineages in hypertension may present novel opportunities to optimize the therapeutic benefits of ARBs. For example, T lymphocytes make important contributions to the induction and progression of various cardiovascular diseases, but new experiments indicate that activation of AT1 receptors on T cells paradoxically limits inflammation and target organ damage in hypertension. Future studies should illustrate how these discrepant functions of AT1 receptors in target organs versus mononuclear cells can be exploited for the benefit of patients with recalcitrant hypertension and other cardiovascular diseases. © 2012 Springer Science+Business Media New York.

Authors
Zhang, J; Crowley, SD
MLA Citation
Zhang, J, and Crowley, SD. "The role of type 1 angiotensin receptors on t lymphocytes in cardiovascular and renal diseases." Current Hypertension Reports 15.1 (2013): 39-46.
Source
scival
Published In
Current Hypertension Reports
Volume
15
Issue
1
Publish Date
2013
Start Page
39
End Page
46
DOI
10.1007/s11906-012-0318-z

The Renin-Angiotensin System

Authors
Le, TH; Crowley, SD; Gurley, SB; Coffman, TM
MLA Citation
Le, TH, Crowley, SD, Gurley, SB, and Coffman, TM. "The Renin-Angiotensin System." Seldin and Geibisch's The Kidney 1 (2013): 427-450.
Source
scival
Published In
Seldin and Geibisch's The Kidney
Volume
1
Publish Date
2013
Start Page
427
End Page
450
DOI
10.1016/B978-0-12-381462-3.00015-X

A novel role for type 1 angiotensin receptors on T lymphocytes to limit target organ damage in hypertension.

RATIONALE: Human clinical trials using type 1 angiotensin (AT(1)) receptor antagonists indicate that angiotensin II is a critical mediator of cardiovascular and renal disease. However, recent studies have suggested that individual tissue pools of AT(1) receptors may have divergent effects on target organ damage in hypertension. OBJECTIVE: We examined the role of AT(1) receptors on T lymphocytes in the pathogenesis of hypertension and its complications. METHODS AND RESULTS: Deficiency of AT(1) receptors on T cells potentiated kidney injury during hypertension with exaggerated renal expression of chemokines and enhanced accumulation of T cells in the kidney. Kidneys and purified CD4(+) T cells from "T cell knockout" mice lacking AT(1) receptors on T lymphocytes had augmented expression of Th1-associated cytokines including interferon-γ and tumor necrosis factor-α. Within T lymphocytes, the transcription factors T-bet and GATA-3 promote differentiation toward the Th1 and Th2 lineages, respectively, and AT(1) receptor-deficient CD4(+) T cells had enhanced T-bet/GATA-3 expression ratios favoring induction of the Th1 response. Inversely, mice that were unable to mount a Th1 response due to T-bet deficiency were protected from kidney injury in our hypertension model. CONCLUSIONS: The current studies identify an unexpected role for AT(1) receptors on T lymphocytes to protect the kidney in the setting of hypertension by favorably modulating CD4(+) T helper cell differentiation.

Authors
Zhang, J-D; Patel, MB; Song, Y-S; Griffiths, R; Burchette, J; Ruiz, P; Sparks, MA; Yan, M; Howell, DN; Gomez, JA; Spurney, RF; Coffman, TM; Crowley, SD
MLA Citation
Zhang, J-D, Patel, MB, Song, Y-S, Griffiths, R, Burchette, J, Ruiz, P, Sparks, MA, Yan, M, Howell, DN, Gomez, JA, Spurney, RF, Coffman, TM, and Crowley, SD. "A novel role for type 1 angiotensin receptors on T lymphocytes to limit target organ damage in hypertension." Circ Res 110.12 (June 8, 2012): 1604-1617.
PMID
22534490
Source
pubmed
Published In
Circulation Research
Volume
110
Issue
12
Publish Date
2012
Start Page
1604
End Page
1617
DOI
10.1161/CIRCRESAHA.111.261768

Recent advances involving the renin-angiotensin system.

The renin-angiotensin system (RAS) exercises fundamental control over sodium and water handling in the kidney. Accordingly, dysregulation of the RAS leads to blood pressure elevation with ensuing renal and cardiovascular damage. Recent studies have revealed that the RAS hormonal cascade is more complex than initially posited with multiple enzymes, effector molecules, and receptors that coordinately regulate the effects of the RAS on the kidney and vasculature. Moreover, recently identified tissue-specific RAS components have pleomorphic effects independent of the circulating RAS that influence critical homeostatic mechanisms including the immune response and fetal development. Further characterization of the diverse interactions between the RAS and other signaling pathways within specific tissues should lead to novel treatments for renal and cardiovascular disease.

Authors
Crowley, SD; Coffman, TM
MLA Citation
Crowley, SD, and Coffman, TM. "Recent advances involving the renin-angiotensin system." Exp Cell Res 318.9 (May 15, 2012): 1049-1056. (Review)
PMID
22410251
Source
pubmed
Published In
Experimental Cell Research
Volume
318
Issue
9
Publish Date
2012
Start Page
1049
End Page
1056
DOI
10.1016/j.yexcr.2012.02.023

Prehypertension and chronic kidney disease: the ox or the plow?

Nearly ten years ago, practice recommendations supported use of the clinical classification of 'prehypertension' for people with systolic blood pressure of 120-139 mm Hg or diastolic pressure of 80-89 mm Hg. This recommendation was based on observations that these ranges of blood pressure were associated with enhanced cardiovascular and cerebrovascular risks compared with blood pressure less than 120/80 mm Hg. Recent observations, including the report by Yano and colleagues, also suggest that prehypertension is an important risk factor for the development of chronic kidney disease.

Authors
Middleton, JP; Crowley, SD
MLA Citation
Middleton, JP, and Crowley, SD. "Prehypertension and chronic kidney disease: the ox or the plow?." Kidney Int 81.3 (February 2012): 229-232.
PMID
22241558
Source
pubmed
Published In
Kidney international
Volume
81
Issue
3
Publish Date
2012
Start Page
229
End Page
232
DOI
10.1038/ki.2011.393

Taking a sound approach to acute kidney injury

Authors
Crowley, SD
MLA Citation
Crowley, SD. "Taking a sound approach to acute kidney injury." American Journal of Physiology - Renal Physiology 303.11 (2012): F1505-F1506.
PMID
22993070
Source
scival
Published In
American journal of physiology. Renal physiology
Volume
303
Issue
11
Publish Date
2012
Start Page
F1505
End Page
F1506
DOI
10.1152/ajprenal.00519.2012

Role of AT₁ receptor-mediated salt retention in angiotensin II-dependent hypertension.

Activation of type 1 angiotensin II (AT(1)) receptors in the kidney promotes blood pressure elevation and target organ damage, but whether renal AT(1) receptors influence the level of hypertension by stimulating sodium retention or by raising systemic vascular resistance has not been established. In the current studies, we used a kidney cross-transplantation strategy to determine whether increased sodium reabsorption by AT(1) receptors in the kidney mediates the chronic hypertensive response to angiotensin II. We found this to be true. In addition, we also identified a second, nontrivial component of blood pressure elevation induced by activation of renal AT(1) receptors that is sodium-independent. As the kidney has the capacity to limit the transmission of elevated systemic blood pressure into the renal microcirculation, prior studies struggled to clearly discriminate the relative contributions of blood pressure elevation vs. activation of AT(1) receptors to hypertensive kidney injury. In our model, we found that rapid surges in blood pressure, which may overcome the kidney's capacity to prevent perturbations in renal hemodynamics, correlate closely with kidney damage in hypertension. Moreover, maximal kidney injury in hypertension may require activation of a pool of nonrenal, systemic AT(1) receptors. These studies provide insight into precise mechanisms through which AT(1) receptor blockade influences the progression of hypertensive kidney disease.

Authors
Crowley, SD; Zhang, J; Herrera, M; Griffiths, R; Ruiz, P; Coffman, TM
MLA Citation
Crowley, SD, Zhang, J, Herrera, M, Griffiths, R, Ruiz, P, and Coffman, TM. "Role of AT₁ receptor-mediated salt retention in angiotensin II-dependent hypertension." Am J Physiol Renal Physiol 301.5 (November 2011): F1124-F1130.
PMID
21849491
Source
pubmed
Published In
American journal of physiology. Renal physiology
Volume
301
Issue
5
Publish Date
2011
Start Page
F1124
End Page
F1130
DOI
10.1152/ajprenal.00305.2011

Comments on Point:Counterpoint: The dominant contributor to systemic hypertension: Chronic activation of the sympathetic nervous system vs. Activation of the intrarenal renin-angiotensin system. AT1 receptors in the kidney mediate the chronic hypertensive response to angiotensin II.

Authors
Crowley, SD
MLA Citation
Crowley, SD. "Comments on Point:Counterpoint: The dominant contributor to systemic hypertension: Chronic activation of the sympathetic nervous system vs. Activation of the intrarenal renin-angiotensin system. AT1 receptors in the kidney mediate the chronic hypertensive response to angiotensin II." J Appl Physiol (1985) 109.6 (December 2010): 2012-2013.
PMID
21188828
Source
pubmed
Published In
Journal of applied physiology (Bethesda, Md. : 1985)
Volume
109
Issue
6
Publish Date
2010
Start Page
2012
End Page
2013

Gene expression profiles linked to AT1 angiotensin receptors in the kidney.

To characterize gene expression networks linked to AT(1) angiotensin receptors in the kidney, we carried out genome-wide transcriptional analysis of RNA from kidneys of wild-type (WT) and AT(1A) receptor-deficient mice (KOs) at baseline and after 2 days of angiotensin II infusion (1,000 ng·kg(-1)·min(-1)). At baseline, 405 genes were differentially expressed (>1.5×) between WT and KO kidneys. Of these, >80% were upregulated in the KO group including genes involved in inflammation, oxidative stress, and cell proliferation. After 2 days of angiotensin II infusion in WT mice, expression of ≈805 genes was altered (18% upregulated, 82% repressed). Genes in metabolism and ion transport pathways were upregulated while there was attenuated expression of genes protective against oxidative stress including glutathione synthetase and mitochondrial superoxide dismutase 2. Angiotensin II infusion had little effect on blood pressure in KOs. Nonetheless, expression of >250 genes was altered in kidneys from KO mice during angiotensin II infusion; 14% were upregulated, while 86% were repressed including genes involved in immune responses, angiogenesis, and glutathione metabolism. Between WT and KO kidneys during angiotensin II infusion, 728 genes were differentially expressed; 10% were increased and 90% were decreased in the WT group. Differentially regulated pathways included those involved in ion transport, immune responses, metabolism, apoptosis, cell proliferation, and oxidative stress. This genome-wide assessment should facilitate identification of critical distal pathways linked to blood pressure regulation.

Authors
Makhanova, NA; Crowley, SD; Griffiths, RC; Coffman, TM
MLA Citation
Makhanova, NA, Crowley, SD, Griffiths, RC, and Coffman, TM. "Gene expression profiles linked to AT1 angiotensin receptors in the kidney." Physiol Genomics 42A.3 (November 15, 2010): 211-218.
PMID
20807774
Source
pubmed
Published In
Physiological genomics
Volume
42A
Issue
3
Publish Date
2010
Start Page
211
End Page
218
DOI
10.1152/physiolgenomics.00063.2010

Lymphocyte responses exacerbate angiotensin II-dependent hypertension.

Activation of the immune system by ANG II contributes to the pathogenesis of hypertension, and pharmacological suppression of lymphocyte responses can ameliorate hypertensive end-organ damage. Therefore, to examine the mechanisms through which lymphocytes mediate blood pressure elevation, we studied ANG II-dependent hypertension in scid mice lacking lymphocyte responses and wild-type controls. Scid mice had a blunted hypertensive response to chronic ANG II infusion and accordingly developed less cardiac hypertrophy. Moreover, lymphocyte deficiency led to significant reductions in heart and kidney injury following 4 wk of angiotensin. The muted hypertensive response in the scid mice was associated with increased sodium excretion, urine volumes, and weight loss beginning on day 5 of angiotensin infusion. To explore the mechanisms underlying alterations in blood pressure and renal sodium handling, we measured gene expression for vasoactive mediators in the kidney after 4 wk of ANG II administration. Scid mice and controls had similar renal expression for interferon-gamma, interleukin-1beta, and interleukin-6. By contrast, lymphocyte deficiency (i.e., scid mice) during ANG II infusion led to upregulation of tumor necrosis factor-alpha, endothelial nitric oxide synthase (eNOS), and cyclooxygenase-2 (COX-2) in the kidney. In turn, this enhanced eNOS and COX-2 expression in the scid kidneys was associated with exaggerated renal generation of nitric oxide, prostaglandin E(2), and prostacyclin, all of which promote natriuresis. Thus, the absence of lymphocyte activity protects from hypertension by allowing blood pressure-induced sodium excretion, possibly via stimulation of eNOS- and COX-2-dependent pathways.

Authors
Crowley, SD; Song, Y-S; Lin, EE; Griffiths, R; Kim, H-S; Ruiz, P
MLA Citation
Crowley, SD, Song, Y-S, Lin, EE, Griffiths, R, Kim, H-S, and Ruiz, P. "Lymphocyte responses exacerbate angiotensin II-dependent hypertension." Am J Physiol Regul Integr Comp Physiol 298.4 (April 2010): R1089-R1097.
PMID
20147609
Source
pubmed
Published In
American journal of physiology. Regulatory, integrative and comparative physiology
Volume
298
Issue
4
Publish Date
2010
Start Page
R1089
End Page
R1097
DOI
10.1152/ajpregu.00373.2009

A role for angiotensin II type 1 receptors on bone marrow-derived cells in the pathogenesis of angiotensin II-dependent hypertension.

Activation of type 1 angiotensin (AT(1)) receptors causes hypertension, leading to progressive kidney injury. AT(1) receptors are expressed on immune cells, and previous studies have identified a role for immune cells in angiotensin II-dependent hypertension. We, therefore, examined the role of AT(1) receptors on immune cells in the pathogenesis of hypertension by generating bone marrow chimeras with wild-type donors or donors lacking AT(1A) receptors (BMKO). The 2 groups had virtually identical blood pressures at baseline, suggesting that AT(1) receptors on immune cells do not make a unique contribution to the determination of baseline blood pressure. By contrast, in response to chronic angiotensin II infusion, the BMKOs had an augmented hypertensive response, suggesting a protective effect of AT(1) receptors on immune cells with respect to blood pressure elevation. The BMKOs had 50% more albuminuria after 4 weeks of angiotensin II-dependent hypertension. Angiotensin II-induced pathological injury to the kidney was similar in the experimental groups. However, there was exaggerated renal expression of the macrophage chemokine monocyte chemoattractant protein 1 in the BMKO group, leading to persistent accumulation of macrophages in the kidney. This enhanced mononuclear cell infiltration into the BMKO kidneys was associated with exaggerated renal expression of the vasoactive mediators interleukin-1beta and interleukin-6. Thus, in angiotensin II-induced hypertension, bone marrow-derived AT(1) receptors limited mononuclear cell accumulation in the kidney and mitigated the chronic hypertensive response, possibly through the regulation of vasoactive cytokines.

Authors
Crowley, SD; Song, Y-S; Sprung, G; Griffiths, R; Sparks, M; Yan, M; Burchette, JL; Howell, DN; Lin, EE; Okeiyi, B; Stegbauer, J; Yang, Y; Tharaux, P-L; Ruiz, P
MLA Citation
Crowley, SD, Song, Y-S, Sprung, G, Griffiths, R, Sparks, M, Yan, M, Burchette, JL, Howell, DN, Lin, EE, Okeiyi, B, Stegbauer, J, Yang, Y, Tharaux, P-L, and Ruiz, P. "A role for angiotensin II type 1 receptors on bone marrow-derived cells in the pathogenesis of angiotensin II-dependent hypertension." Hypertension 55.1 (January 2010): 99-108.
PMID
19996062
Source
pubmed
Published In
Hypertension
Volume
55
Issue
1
Publish Date
2010
Start Page
99
End Page
108
DOI
10.1161/HYPERTENSIONAHA.109.144964

Simulation of lymphoctye responses by angiotensin II promotes kidney injury in hypertension (American Journal Physiology-Renal Physiology (2008) 295, (F515-F524))

Authors
Crowley, SD; Frey, CW; Gould, SK; Griffiths, R; Ruiz, P; Burchette, JL; Howell, DN; Makhanova, N; Yan, M; Kim, H-S; Tharaux, P-L; Coffman, TM
MLA Citation
Crowley, SD, Frey, CW, Gould, SK, Griffiths, R, Ruiz, P, Burchette, JL, Howell, DN, Makhanova, N, Yan, M, Kim, H-S, Tharaux, P-L, and Coffman, TM. "Simulation of lymphoctye responses by angiotensin II promotes kidney injury in hypertension (American Journal Physiology-Renal Physiology (2008) 295, (F515-F524))." American Journal of Physiology - Renal Physiology 298.5 (2010): F1286-.
Source
scival
Published In
American journal of physiology. Renal physiology
Volume
298
Issue
5
Publish Date
2010
Start Page
F1286
DOI
10.1152/ajprenal.zh2-5901-corr.2010

Comments on Point:Counterpoint: The dominant contributor to systemic hypertension: Chronic activation of the sympathetic nervous system vs. Activation of the intrarenal renin-angiotensin system. Activated intrarenal renin-angiotensin system is correlated with high blood pressure in humans.

Authors
Kobori, H; Fu, Q; Crowley, SD; Gonzalez-Villalobos, RA; Campos, RR
MLA Citation
Kobori, H, Fu, Q, Crowley, SD, Gonzalez-Villalobos, RA, and Campos, RR. "Comments on Point:Counterpoint: The dominant contributor to systemic hypertension: Chronic activation of the sympathetic nervous system vs. Activation of the intrarenal renin-angiotensin system. Activated intrarenal renin-angiotensin system is correlated with high blood pressure in humans." Journal of applied physiology (Bethesda, Md. : 1985) 109.6 (2010): 2003--.
PMID
21148352
Source
scival
Published In
Journal of applied physiology (Bethesda, Md. : 1985)
Volume
109
Issue
6
Publish Date
2010
Start Page
2003-
DOI
10.1152/japplphysiol.01160.2010

AT1 receptors in the Kidney mediate the chronic hypertensive response to angiotensin II

Authors
Crowley, SD
MLA Citation
Crowley, SD. "AT1 receptors in the Kidney mediate the chronic hypertensive response to angiotensin II." Journal of Applied Physiology 109.6 (2010): 2012-2013.
Source
scival
Published In
Journal of applied physiology (Bethesda, Md. : 1985)
Volume
109
Issue
6
Publish Date
2010
Start Page
2012
End Page
2013
DOI
10.1152/japplphysiol.01160.2010

Response to angiotensin II type 1a-deficient bone marrow-derived dendritic cells produce higher levels of monocyte chemoattractant protein 1

Authors
Crowley, SD; Song, Y-S; Sprung, G; Griffiths, R; Sparks, M; Yan, M; Burchette, JL; Howell, DN; Lin, EE; Okeiyi, B; Stegbauer, J; Yang, Y; Tharaux, P-L; Ruiz, P
MLA Citation
Crowley, SD, Song, Y-S, Sprung, G, Griffiths, R, Sparks, M, Yan, M, Burchette, JL, Howell, DN, Lin, EE, Okeiyi, B, Stegbauer, J, Yang, Y, Tharaux, P-L, and Ruiz, P. "Response to angiotensin II type 1a-deficient bone marrow-derived dendritic cells produce higher levels of monocyte chemoattractant protein 1." Hypertension 56.1 (2010): e8-.
Source
scival
Published In
Hypertension
Volume
56
Issue
1
Publish Date
2010
Start Page
e8
DOI
10.1161/HYPERTENSIONAHA.110.153544

Glomerular type 1 angiotensin receptors augment kidney injury and inflammation in murine autoimmune nephritis.

Studies in humans and animal models indicate a key contribution of angiotensin II to the pathogenesis of glomerular diseases. To examine the role of type 1 angiotensin (AT1) receptors in glomerular inflammation associated with autoimmune disease, we generated MRL-Faslpr/lpr (lpr) mice lacking the major murine type 1 angiotensin receptor (AT1A); lpr mice develop a generalized autoimmune disease with glomerulonephritis that resembles SLE. Surprisingly, AT1A deficiency was not protective against disease but instead substantially accelerated mortality, proteinuria, and kidney pathology. Increased disease severity was not a direct effect of immune cells, since transplantation of AT1A-deficient bone marrow did not affect survival. Moreover, autoimmune injury in extrarenal tissues, including skin, heart, and joints, was unaffected by AT1A deficiency. In murine systems, there is a second type 1 angiotensin receptor isoform, AT1B, and its expression is especially prominent in the renal glomerulus within podocytes. Further, expression of renin was enhanced in kidneys of AT1A-deficient lpr mice, and they showed evidence of exaggerated AT1B receptor activation, including substantially increased podocyte injury and expression of inflammatory mediators. Administration of losartan, which blocks all type 1 angiotensin receptors, reduced markers of kidney disease, including proteinuria, glomerular pathology, and cytokine mRNA expression. Since AT1A-deficient lpr mice had low blood pressure, these findings suggest that activation of type 1 angiotensin receptors in the glomerulus is sufficient to accelerate renal injury and inflammation in the absence of hypertension.

Authors
Crowley, SD; Vasievich, MP; Ruiz, P; Gould, SK; Parsons, KK; Pazmino, AK; Facemire, C; Chen, BJ; Kim, H-S; Tran, TT; Pisetsky, DS; Barisoni, L; Prieto-Carrasquero, MC; Jeansson, M; Foster, MH; Coffman, TM
MLA Citation
Crowley, SD, Vasievich, MP, Ruiz, P, Gould, SK, Parsons, KK, Pazmino, AK, Facemire, C, Chen, BJ, Kim, H-S, Tran, TT, Pisetsky, DS, Barisoni, L, Prieto-Carrasquero, MC, Jeansson, M, Foster, MH, and Coffman, TM. "Glomerular type 1 angiotensin receptors augment kidney injury and inflammation in murine autoimmune nephritis." J Clin Invest 119.4 (April 2009): 943-953.
PMID
19287096
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
119
Issue
4
Publish Date
2009
Start Page
943
End Page
953
DOI
10.1172/JCI34862

The Renin-Angiotensin System

Authors
Thu H, L; Steven D, C; Susan B, G; Thomas M, C
MLA Citation
Thu H, L, Steven D, C, Susan B, G, and Thomas M, C. "The Renin-Angiotensin System." (December 1, 2008): 343-357. (Chapter)
Source
scopus
Publish Date
2008
Start Page
343
End Page
357
DOI
10.1016/B978-012088488-9.50016-4

In hypertension, the kidney breaks your heart.

The renin-angiotensin system (RAS) is a master regulator of blood pressure and fluid homeostasis. Because RAS components are expressed in several tissues that may influence blood pressure, studies using conventional gene targeting to globally interrupt the RAS have not determined the contributions of angiotensin II receptor type 1 (AT(1)) receptors in specific tissue pools to blood pressure regulation and tissue injury. Recent experiments using kidney cross-transplantation and mice lacking the dominant murine AT(1) receptor isoform, AT(1A), have demonstrated that 1) AT(1) receptors inside and outside the kidney make equivalent contributions to normal blood pressure homeostasis, 2) activation of renal AT(1) receptors is required for the development of angiotensin II-dependent hypertension, and 3) this blood pressure elevation rather than activation of AT(1) receptors in the heart drives angiotensin II-induced cardiac hypertrophy. These findings, together with previous experiments, confirm the kidney's critical role in the pathogenesis of hypertension and its complications.

Authors
Crowley, SD; Coffman, TM
MLA Citation
Crowley, SD, and Coffman, TM. "In hypertension, the kidney breaks your heart." Curr Cardiol Rep 10.6 (November 2008): 470-476. (Review)
PMID
18950556
Source
pubmed
Published In
Current Cardiology Reports
Volume
10
Issue
6
Publish Date
2008
Start Page
470
End Page
476

Stimulation of lymphocyte responses by angiotensin II promotes kidney injury in hypertension.

Activation of the renin-angiotensin system contributes to the progression of chronic kidney disease. Based on the known cellular effects of ANG II to promote inflammation, we posited that stimulation of lymphocyte responses by ANG II might contribute to the pathogenesis of hypertensive kidney injury. We therefore examined the effects of the immunosuppressive agent mycophenolate mofetil (MMF) on the course of hypertension and kidney disease induced by chronic infusion of ANG II in 129/SvEv mice. Although it had no effect on the severity of hypertension or cardiac hypertrophy, treatment with MMF significantly reduced albuminuria and ameliorated kidney injury, decreasing glomerulosclerosis and reducing lymphocyte infiltration into the renal interstitium. Attenuation of renal pathology with MMF was associated with reduced expression of mRNAs for the proinflammatory cytokines interferon-gamma and tumor necrosis factor-alpha and the profibrotic cytokine transforming growth factor-beta. As infiltration of the kidney by T lymphocytes was a prominent feature of ANG II-dependent renal injury, we carried out experiments examining the effects of ANG II on lymphocytes in vitro. We find that exposure of splenic lymphocytes to ANG II causes prominent rearrangements of the actin cytoskeleton. These actions require the activity of Rho kinase. Thus, ANG II exaggerates hypertensive kidney injury by stimulating lymphocyte responses. These proinflammatory actions of ANG II seem to have a proclivity for inducing kidney injury while having negligible actions in the pathogenesis of cardiac hypertrophy.

Authors
Crowley, SD; Frey, CW; Gould, SK; Griffiths, R; Ruiz, P; Burchette, JL; Howell, DN; Makhanova, N; Yan, M; Kim, H-S; Tharaux, P-L; Coffman, TM
MLA Citation
Crowley, SD, Frey, CW, Gould, SK, Griffiths, R, Ruiz, P, Burchette, JL, Howell, DN, Makhanova, N, Yan, M, Kim, H-S, Tharaux, P-L, and Coffman, TM. "Stimulation of lymphocyte responses by angiotensin II promotes kidney injury in hypertension." Am J Physiol Renal Physiol 295.2 (August 2008): F515-F524.
PMID
18495795
Source
pubmed
Published In
American Journal of Physiology: Renal Physiology
Volume
295
Issue
2
Publish Date
2008
Start Page
F515
End Page
F524
DOI
10.1152/ajprenal.00527.2007

Kidney in hypertension: guyton redux.

Authors
Coffman, TM; Crowley, SD
MLA Citation
Coffman, TM, and Crowley, SD. "Kidney in hypertension: guyton redux." Hypertension 51.4 (April 2008): 811-816. (Review)
PMID
18332286
Source
pubmed
Published In
Hypertension
Volume
51
Issue
4
Publish Date
2008
Start Page
811
End Page
816
DOI
10.1161/HYPERTENSIONAHA.105.063636

In hypertension, the kidney rules.

The renin-angiotensin system (RAS) is a critical regulator of blood pressure and fluid homeostasis. Components of the RAS, including renin, angiotensin-converting enzyme (ACE), and angiotensin type 1 (AT1) receptors, are expressed throughout the body in tissues that may impact blood pressure control. Blocking actions of individual components of the RAS lowers blood pressure. Although it has been suggested that control of sodium excretion by the kidney is the dominant mechanism for blood pressure regulation by the RAS, pharmacologic antagonists or conventional gene targeting experiments globally interrupt the RAS and cannot discriminate its actions in the kidney from other tissue compartments. Recent experiments using kidney cross-transplantation and genetically engineered mice have confirmed a major role for angiotensin II acting via AT1 receptors in the kidney in hypertension. These actions of renal AT1 receptors are required for the development of angiotensin II-dependent hypertension and cardiac hypertrophy. These findings, with previous experiments, clearly establish the critical role of the kidney in the pathogenesis of hypertension and its cardiovascular complications.

Authors
Crowley, SD; Coffman, TM
MLA Citation
Crowley, SD, and Coffman, TM. "In hypertension, the kidney rules." Curr Hypertens Rep 9.2 (April 2007): 148-153. (Review)
PMID
17442227
Source
pubmed
Published In
Current Hypertension Reports
Volume
9
Issue
2
Publish Date
2007
Start Page
148
End Page
153

AT(1) receptors and control of blood pressure: the kidney and more...

The renin-angiotensin system (RAS) is a critical regulator of blood pressure and fluid homeostasis. The components of the RAS including renin, angiotensin-converting enzyme, and angiotensin receptors are expressed throughout the body in tissues that may impact blood pressure control. Blocking actions of individual components of the RAS including renin, angiotensin-converting enzyme, or the type 1 (AT(1)) receptor lowers blood pressure. Although it has been suggested that control of sodium excretion by the kidney is the dominant mechanism for blood pressure regulation by the RAS, pharmacologic antagonists or conventional gene-targeting experiments globally interrupt the RAS and cannot discriminate its actions in the kidney from other tissue compartments. Recent experiments with the use of kidney cross-transplantation and genetically engineered mice suggest independent and equivalent effects of angiotensin II acting via AT(1) receptors in the kidney and in extrarenal tissues to maintain the normal level of blood pressure. However, the nature and relative contributions of these actions may differ in hypertension.

Authors
Crowley, SD; Gurley, SB; Coffman, TM
MLA Citation
Crowley, SD, Gurley, SB, and Coffman, TM. "AT(1) receptors and control of blood pressure: the kidney and more.." Trends Cardiovasc Med 17.1 (January 2007): 30-34. (Review)
PMID
17210476
Source
pubmed
Published In
Trends in Cardiovascular Medicine
Volume
17
Issue
1
Publish Date
2007
Start Page
30
End Page
34
DOI
10.1016/j.tcm.2006.11.002

Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney.

Essential hypertension is a common disease, yet its pathogenesis is not well understood. Altered control of sodium excretion in the kidney may be a key causative feature, but this has been difficult to test experimentally, and recent studies have challenged this hypothesis. Based on the critical role of the renin-angiotensin system (RAS) and the type I (AT1) angiotensin receptor in essential hypertension, we developed an experimental model to separate AT1 receptor pools in the kidney from those in all other tissues. Although actions of the RAS in a variety of target organs have the potential to promote high blood pressure and end-organ damage, we show here that angiotensin II causes hypertension primarily through effects on AT1 receptors in the kidney. We find that renal AT1 receptors are absolutely required for the development of angiotensin II-dependent hypertension and cardiac hypertrophy. When AT1 receptors are eliminated from the kidney, the residual repertoire of systemic, extrarenal AT1 receptors is not sufficient to induce hypertension or cardiac hypertrophy. Our findings demonstrate the critical role of the kidney in the pathogenesis of hypertension and its cardiovascular complications. Further, they suggest that the major mechanism of action of RAS inhibitors in hypertension is attenuation of angiotensin II effects in the kidney.

Authors
Crowley, SD; Gurley, SB; Herrera, MJ; Ruiz, P; Griffiths, R; Kumar, AP; Kim, H-S; Smithies, O; Le, TH; Coffman, TM
MLA Citation
Crowley, SD, Gurley, SB, Herrera, MJ, Ruiz, P, Griffiths, R, Kumar, AP, Kim, H-S, Smithies, O, Le, TH, and Coffman, TM. "Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney." Proc Natl Acad Sci U S A 103.47 (November 21, 2006): 17985-17990.
PMID
17090678
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
103
Issue
47
Publish Date
2006
Start Page
17985
End Page
17990
DOI
10.1073/pnas.0605545103

Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin-angiotensin system.

Angiotensin II, acting through type 1 angiotensin (AT(1)) receptors, has potent effects that alter renal excretory mechanisms. Control of sodium excretion by the kidney has been suggested to be the critical mechanism for blood pressure regulation by the renin-angiotensin system (RAS). However, since AT(1) receptors are ubiquitously expressed, precisely dissecting their physiological actions in individual tissue compartments including the kidney with conventional pharmacological or gene targeting experiments has been difficult. Here, we used a cross-transplantation strategy and AT(1A) receptor-deficient mice to demonstrate distinct and virtually equivalent contributions of AT(1) receptor actions in the kidney and in extrarenal tissues to determining the level of blood pressure. We demonstrate that regulation of blood pressure by extrarenal AT(1A) receptors cannot be explained by altered aldosterone generation, which suggests that AT(1) receptor actions in systemic tissues such as the vascular and/or the central nervous systems make nonredundant contributions to blood pressure regulation. We also show that interruption of the AT(1) receptor-mediated short-loop feedback in the kidney is not sufficient to explain the marked stimulation of renin production induced by global AT(1) receptor deficiency or by receptor blockade. Instead, the renin response seems to be primarily determined by renal baroreceptor mechanisms triggered by reduced blood pressure. Thus, the regulation of blood pressure by the RAS is mediated by AT(1) receptors both within and outside the kidney.

Authors
Crowley, SD; Gurley, SB; Oliverio, MI; Pazmino, AK; Griffiths, R; Flannery, PJ; Spurney, RF; Kim, H-S; Smithies, O; Le, TH; Coffman, TM
MLA Citation
Crowley, SD, Gurley, SB, Oliverio, MI, Pazmino, AK, Griffiths, R, Flannery, PJ, Spurney, RF, Kim, H-S, Smithies, O, Le, TH, and Coffman, TM. "Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin-angiotensin system." J Clin Invest 115.4 (April 2005): 1092-1099.
PMID
15841186
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
115
Issue
4
Publish Date
2005
Start Page
1092
End Page
1099
DOI
10.1172/JCI23378

Exploring type I angiotensin (AT1) receptor functions through gene targeting.

The renin-angiotensin system (RAS) modulates a diverse set of physiological processes including development, blood pressure, renal function and inflammation. The principal effector molecule of this system, angiotensin II, mediates most of these actions. The classically recognized functions of the RAS are triggered via the type 1 (AT(1)) class of angiotensin receptors. Pharmacological blockade of the AT(1) receptor lowers blood pressure and slows the progression of cardiovascular and renal diseases. Gene-targeting technology provides an experimental approach for precisely dissecting the physiological functions of the RAS. Here, we review how gene-targeting experiments have elucidated AT(1) receptor functions.

Authors
Crowley, SD; Tharaux, P-L; Audoly, LP; Coffman, TM
MLA Citation
Crowley, SD, Tharaux, P-L, Audoly, LP, and Coffman, TM. "Exploring type I angiotensin (AT1) receptor functions through gene targeting." Acta Physiol Scand 181.4 (August 2004): 561-570. (Review)
PMID
15283771
Source
pubmed
Published In
Acta physiologica Scandinavica
Volume
181
Issue
4
Publish Date
2004
Start Page
561
End Page
570
DOI
10.1111/j.1365-201X.2004.01331.x

Effector mechanisms in transplant rejection.

Antigens, provided by the allograft, trigger the activation and proliferation of allospecific T cells. As a consequence of this response, effector elements are generated that mediate graft injury and are responsible for the clinical manifestations of allograft rejection. Donor-specific CD8+ cytotoxic T lymphocytes play a major role in this process. Likewise, CD4+ T cells mediate delayed-type hypersensitivity responses via the production of soluble mediators that function to further activate and guide immune cells to the site of injury. In addition, these mediators may directly alter graft function by modulating vascular tone and permeability or by promoting platelet aggregation. Allospecific CD4+ T cells also promote B-cell maturation and differentiation into antibody-secreting plasma cells via CD40-CD40 ligand interactions. Alloantibodies that are produced by these B cells exert most of their detrimental effects on the graft by activating the complement cascade. Alternatively, antibodies can bind Fc receptors on natural killer cells or macrophages and cause target cell lysis via antibody-dependent cell-mediated cytotoxicity. In this review, we discuss these major effector pathways, focusing on their role in the pathogenesis of allograft rejection.

Authors
Rocha, PN; Plumb, TJ; Crowley, SD; Coffman, TM
MLA Citation
Rocha, PN, Plumb, TJ, Crowley, SD, and Coffman, TM. "Effector mechanisms in transplant rejection." Immunol Rev 196 (December 2003): 51-64. (Review)
PMID
14617197
Source
pubmed
Published In
Immunological Reviews
Volume
196
Publish Date
2003
Start Page
51
End Page
64

Rho kinase promotes alloimmune responses by regulating the proliferation and structure of T cells.

Coordinated rearrangements of the actin-myosin cytoskeleton facilitate early and late events in T cell activation and signal transduction. As many important features of cell shape rearrangement involve small GTP-binding proteins, we examined the contribution of Rho kinase to the functions of mature T cells. Inhibitors of the Rho kinase pathway all had similar actions to inhibit the proliferation of primary lymphocyte cultures. Likewise, transfection of the human Jurkat T cell line with a dominant negative, kinase-defective mutant of Rho kinase diminished Jurkat cell proliferation. Furthermore, inhibition of Rho kinase substantially attenuated the program of cytokine gene expression that characterizes T cell activation, blocked actomyosin polymerization, and prevented aggregation of the TCR/CD3 complex colocalized with lipid rafts. These actions are relevant to immune responses in vivo, as treatment with a Rho kinase inhibitor considerably prolonged the survival of fully allogeneic heart transplants in mice and diminished intragraft expression of cytokine mRNAs. Thus, Rho GTPases acting through Rho kinase play a unique role in T cell activation during cellular immune responses by promoting structural rearrangements that are critical for T cell signaling.

Authors
Tharaux, P-L; Bukoski, RC; Rocha, PN; Crowley, SD; Ruiz, P; Nataraj, C; Howell, DN; Kaibuchi, K; Spurney, RF; Coffman, TM
MLA Citation
Tharaux, P-L, Bukoski, RC, Rocha, PN, Crowley, SD, Ruiz, P, Nataraj, C, Howell, DN, Kaibuchi, K, Spurney, RF, and Coffman, TM. "Rho kinase promotes alloimmune responses by regulating the proliferation and structure of T cells." J Immunol 171.1 (July 1, 2003): 96-105.
PMID
12816987
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
171
Issue
1
Publish Date
2003
Start Page
96
End Page
105

A Web-based compendium of clinical questions and medical evidence to educate internal medicine residents.

The authors designed an electronic database of clinical questions (CQs) and medical evidence and implemented it in 2001-02 at Duke University Medical Center and the Veterans Administration Medical Center in Durham, North Carolina. This Web-based data collection system is called the Critical Appraisal Resource (CAR) and is still in operation. This report is of ten months of the system's operation. During their medicine ward rotations, residents entered CQs into the CAR; they also entered Medline reference links and validated article summaries. Residents' utilization of the CAR database, Medline, and other electronic resources was prospectively measured. In addition, residents were prospectively surveyed regarding the impact of each question and associated reference on medical decision making for individual patients. Over ten months, residents entered 625 patient-based CQs into the CAR and were able to obtain useful information from the medical literature on 82% of the CQs they searched. The two most prevalent CQ types were therapy and diagnosis questions (53% and 22%). Sixty percent of the therapy articles considered useful were reports of randomized controlled trials. Residents obtained 77% of their useful data from Medline. They reported that obtaining useful data altered patient management 47% of the time. Residents used the CAR as a resource, searching the database for information 1,035 times over the study period. In summary, the use of an evidence-based critical appraisal resource led residents to engage the medical literature on behalf of their patients and influenced approximately half of their patient-care decisions. Residents benefited from questions previously searched by other residents, allowing them to address a wider spectrum of CQs during ward rotations.

Authors
Crowley, SD; Owens, TA; Schardt, CM; Wardell, SI; Peterson, J; Garrison, S; Keitz, SA
MLA Citation
Crowley, SD, Owens, TA, Schardt, CM, Wardell, SI, Peterson, J, Garrison, S, and Keitz, SA. "A Web-based compendium of clinical questions and medical evidence to educate internal medicine residents." Acad Med 78.3 (March 2003): 270-274. (Review)
PMID
12634206
Source
pubmed
Published In
Academic Medicine
Volume
78
Issue
3
Publish Date
2003
Start Page
270
End Page
274

Coronary steal from a left internal mammary artery coronary bypass graft by a left upper extremity arteriovenous hemodialysis fistula.

In patients with end-stage renal disease undergoing hemodialysis, the upper extremity arteriovenous (AV) fistula is the dialysis access recommended by the DOQI guidelines for patients with appropriate vasculature. Upper extremity AV fistulae have long periods of usefulness, high flow rates, and low associated complication rates. Placement of AV access may result in increased cardiac output and increased cardiac oxygen demand in these patients. In general, cardiovascular complications from AV access have been limited. We report a novel cardiovascular complication of AV access in an end-stage renal disease patient with a coronary artery bypass graft employing the left internal mammary artery who experienced angina while undergoing hemodialysis. The angina was mediated at least in part by cardiac catheterization laboratory-documented steal of blood flow from the internal mammary artery graft. This phenomenon suggests the need to consider the impact of upper extremity access placement on blood flow to the left internal mammary artery in patients who previously have undergone placement of a coronary artery bypass graft.

Authors
Crowley, SD; Butterly, DW; Peter, RH; Schwab, SJ
MLA Citation
Crowley, SD, Butterly, DW, Peter, RH, and Schwab, SJ. "Coronary steal from a left internal mammary artery coronary bypass graft by a left upper extremity arteriovenous hemodialysis fistula." Am J Kidney Dis 40.4 (October 2002): 852-855.
PMID
12324924
Source
pubmed
Published In
American Journal of Kidney Diseases
Volume
40
Issue
4
Publish Date
2002
Start Page
852
End Page
855
DOI
10.1053/ajkd.2002.35701

Slowing the progression of chronic renal insufficiency.

Authors
Crowley, S
MLA Citation
Crowley, S. "Slowing the progression of chronic renal insufficiency." North Carolina medical journal 61.2 (2000): 80-83.
PMID
10737028
Source
scival
Published In
North Carolina medical journal
Volume
61
Issue
2
Publish Date
2000
Start Page
80
End Page
83

Immunological properties of bacterial DNA.

Authors
Pisetsky, DS; Reich, C; Crowley, SD; Halpern, MD
MLA Citation
Pisetsky, DS, Reich, C, Crowley, SD, and Halpern, MD. "Immunological properties of bacterial DNA." Ann N Y Acad Sci 772 (November 27, 1995): 152-163. (Review)
PMID
8546388
Source
pubmed
Published In
Annals of the New York Academy of Sciences
Volume
772
Publish Date
1995
Start Page
152
End Page
163
Show More