Steven Crowley

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.

Positions:

Professor of Medicine

Medicine, Nephrology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1996

Duke University

Medical Resident, Medicine

Duke University

Fellow in Nephrology, Medicine

Duke University

Chief Medical Resident, Medicine

Duke University

Fellow in Nephrology, Medicine

Duke University

Grants:

The Role of the IL-1 Receptor in the AKI to CKD transition

Administered By
Anesthesiology, Critical Care Medicine
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

The interleukin-1 receptor regulates crosstalk between myeloid and renal tubular cells in hypertension

Administered By
Medicine, Nephrology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

The interleukin-1 receptor modulates blood pressure and renal tubular injury

Administered By
Medicine, Nephrology
Awarded By
American Heart Association
Role
Principal Investigator
Start Date
End Date

IPA extenstion - Robert Griffiths

Administered By
Medicine, Nephrology
Awarded By
Durham Veterans Affairs Medical Center
Role
Principal Investigator
Start Date
End Date

Dendritic cells activate pro-hypertensive T cells to drive sodium reaborption in kidney

Administered By
Medicine, Nephrology
Awarded By
American Heart Association
Role
Principal Investigator
Start Date
End Date

Publications:

INFLAMMATORY PROFILE OF MURINE SEPTIC AKI: ROLE OF CD11C+/CX3CR1+ANTIGEN PRESENTING CELLS

Authors
Privratsky, J; Ren, J; Morris, B; Crowley, SD
MLA Citation
Privratsky, Jamie, et al. “INFLAMMATORY PROFILE OF MURINE SEPTIC AKI: ROLE OF CD11C+/CX3CR1+ANTIGEN PRESENTING CELLS.” Anesthesia and Analgesia, vol. 128, 2019, pp. 206–206.
URI
https://scholars.duke.edu/individual/pub1475944
Source
wos-lite
Published In
Anesthesia and Analgesia
Volume
128
Published Date
Start Page
206
End Page
206

Ferroptotic stress promotes the accumulation of pro-inflammatory proximal tubular cells in maladaptive renal repair

<jats:title>Abstract</jats:title><jats:p>Overwhelming lipid peroxidation induces ferroptotic stress and ferroptosis, a non-apoptotic form of regulated cell death that has been implicated in maladaptive renal repair in mice and humans. Using single-cell transcriptomic and mouse genetic approaches, we show that proximal tubular (PT) cells develop a molecularly distinct, pro-inflammatory state following injury. While these inflammatory PT cells transiently appear after mild injury and return to their original state without inducing fibrosis, they accumulate and contribute to persistent inflammation after severe injury. This transient inflammatory PT state significantly downregulates glutathione metabolism genes, making them vulnerable to ferroptotic stress. Genetic induction of high ferroptotic stress in these cells after mild injury leads to the accumulation of the inflammatory PT cells, enhancing inflammation and fibrosis. Our study broadens the roles of ferroptotic stress from being a trigger of regulated cell death to include the promotion and accumulation of proinflammatory cells that underlie maladaptive repair.</jats:p>
Authors
Ide, S; Kobayashi, Y; Ide, K; Strausser, SA; Herbek, S; O’Brien, LL; Crowley, SD; Barisoni, L; Tata, A; Tata, PR; Souma, T
MLA Citation
Ide, Shintaro, et al. Ferroptotic stress promotes the accumulation of pro-inflammatory proximal tubular cells in maladaptive renal repair. Cold Spring Harbor Laboratory. Crossref, doi:10.1101/2021.03.23.436661.
URI
https://scholars.duke.edu/individual/pub1476506
Source
crossref
DOI
10.1101/2021.03.23.436661

FIH-1-modulated HIF-1α C-TAD promotes acute kidney injury to chronic kidney disease progression via regulating KLF5 signaling.

Incomplete recovery from episodes of acute kidney injury (AKI) can predispose patients to develop chronic kidney disease (CKD). Although hypoxia-inducible factor-1α (HIF-1α) is a master regulator of the response to hypoxia/ischemia, the role of HIF-1α in CKD progression following incomplete recovery from AKI is poorly understood. Here, we investigated this issue using moderate and severe ischemia/reperfusion injury (I/RI) mouse models. We found that the outcomes of AKI were highly associated with the time course of tubular HIF-1α expression. Sustained activation of HIF-1α, accompanied by the development of renal fibrotic lesions, was found in kidneys with severe AKI. The AKI to CKD progression was markedly ameliorated when PX-478 (a specific HIF-1α inhibitor, 5 mg· kg-1·d-1, i.p.) was administered starting on day 5 after severe I/RI for 10 consecutive days. Furthermore, we demonstrated that HIF-1α C-terminal transcriptional activation domain (C-TAD) transcriptionally stimulated KLF5, which promoted progression of CKD following severe AKI. The effect of HIF-1α C-TAD activation on promoting AKI to CKD progression was also confirmed in in vivo and in vitro studies. Moreover, we revealed that activation of HIF-1α C-TAD resulted in the loss of FIH-1, which was the key factor governing HIF-1α-driven AKI to CKD progression. Overexpression of FIH-1 inhibited HIF-1α C-TAD and prevented AKI to CKD progression. Thus, FIH-1-modulated HIF-1α C-TAD activation was the key mechanism of AKI to CKD progression by transcriptionally regulating KLF5 pathway. Our results provide new insights into the role of HIF-1α in AKI to CKD progression and also the potential therapeutic strategy for the prevention of renal diseases progression.
Authors
Li, Z-L; Wang, B; Lv, L-L; Tang, T-T; Wen, Y; Cao, J-Y; Zhu, X-X; Feng, S-T; Crowley, SD; Liu, B-C
MLA Citation
Li, Zuo-Lin, et al. “FIH-1-modulated HIF-1α C-TAD promotes acute kidney injury to chronic kidney disease progression via regulating KLF5 signaling.Acta Pharmacol Sin, Mar. 2021. Pubmed, doi:10.1038/s41401-021-00617-4.
URI
https://scholars.duke.edu/individual/pub1475536
PMID
33658705
Source
pubmed
Published In
Acta Pharmacol Sin
Published Date
DOI
10.1038/s41401-021-00617-4

Direct Actions of AT1 (Type 1 Angiotensin) Receptors in Cardiomyocytes Do Not Contribute to Cardiac Hypertrophy.

Activation of AT1 (type 1 Ang) receptors stimulates cardiomyocyte hypertrophy in vitro. Accordingly, it has been suggested that regression of cardiac hypertrophy associated with renin-Ang system blockade is due to inhibition of cellular actions of Ang II in the heart, above and beyond their effects to reduce pressure overload. We generated 2 distinct mouse lines with cell-specific deletion of AT1A receptors, from cardiomyocytes. In the first line (C-SMKO), elimination of AT1A receptors was achieved using a heterologous Cre recombinase transgene under control of the Sm22 promoter, which expresses in cells of smooth muscle lineage including cardiomyocytes and vascular smooth muscle cells of conduit but not resistance vessels. The second line (R-SMKO) utilized a Cre transgene knocked-in to the Sm22 locus, which drives expression in cardiac myocytes and vascular smooth muscle cells in both conduit and resistance arteries. Thus, although both groups lack AT1 receptors in the cardiomyocytes, they are distinguished by presence (C-SMKO) or absence (R-SMKO) of peripheral vascular responses to Ang II. Similar to wild-types, chronic Ang II infusion caused hypertension and cardiac hypertrophy in C-SMKO mice, whereas both hypertension and cardiac hypertrophy were reduced in R-SMKOs. Thus, despite the absence of AT1A receptors in cardiomyocytes, C-SMKOs develop robust cardiac hypertrophy. By contrast, R-SMKOs developed identical levels of hypertrophy in response to pressure overload-induced by transverse aortic banding. Our findings suggest that direct activation of AT1 receptors in cardiac myocytes has minimal influence on cardiac hypertrophy induced by renin-Ang system activation or pressure overload.
Authors
Sparks, MA; Rianto, F; Diaz, E; Revoori, R; Hoang, T; Bouknight, L; Stegbauer, J; Vivekanandan-Giri, A; Ruiz, P; Pennathur, S; Abraham, DM; Gurley, SB; Crowley, SD; Coffman, TM
MLA Citation
Sparks, Matthew A., et al. “Direct Actions of AT1 (Type 1 Angiotensin) Receptors in Cardiomyocytes Do Not Contribute to Cardiac Hypertrophy.Hypertension, vol. 77, no. 2, Feb. 2021, pp. 393–404. Pubmed, doi:10.1161/HYPERTENSIONAHA.119.14079.
URI
https://scholars.duke.edu/individual/pub1471301
PMID
33390039
Source
pubmed
Published In
Hypertension
Volume
77
Published Date
Start Page
393
End Page
404
DOI
10.1161/HYPERTENSIONAHA.119.14079

Severe Acute Respiratory Syndrome Coronavirus 2, COVID-19, and the Renin-Angiotensin System: Pressing Needs and Best Research Practices.

The coronavirus disease 2019 (COVID-19) pandemic is associated with significant morbidity and mortality throughout the world, predominantly due to lung and cardiovascular injury. The virus responsible for COVID-19-severe acute respiratory syndrome coronavirus 2-gains entry into host cells via ACE2 (angiotensin-converting enzyme 2). ACE2 is a primary enzyme within the key counter-regulatory pathway of the renin-angiotensin system (RAS), which acts to oppose the actions of Ang (angiotensin) II by generating Ang-(1-7) to reduce inflammation and fibrosis and mitigate end organ damage. As COVID-19 spans multiple organ systems linked to the cardiovascular system, it is imperative to understand clearly how severe acute respiratory syndrome coronavirus 2 may affect the multifaceted RAS. In addition, recognition of the role of ACE2 and the RAS in COVID-19 has renewed interest in its role in the pathophysiology of cardiovascular disease in general. We provide researchers with a framework of best practices in basic and clinical research to interrogate the RAS using appropriate methodology, especially those who are relatively new to the field. This is crucial, as there are many limitations inherent in investigating the RAS in experimental models and in humans. We discuss sound methodological approaches to quantifying enzyme content and activity (ACE, ACE2), peptides (Ang II, Ang-[1-7]), and receptors (types 1 and 2 Ang II receptors, Mas receptor). Our goal is to ensure appropriate research methodology for investigations of the RAS in patients with severe acute respiratory syndrome coronavirus 2 and COVID-19 to ensure optimal rigor and reproducibility and appropriate interpretation of results from these investigations.
Authors
Sparks, MA; South, AM; Badley, AD; Baker-Smith, CM; Batlle, D; Bozkurt, B; Cattaneo, R; Crowley, SD; Dell'Italia, LJ; Ford, AL; Griendling, K; Gurley, SB; Kasner, SE; Murray, JA; Nath, KA; Pfeffer, MA; Rangaswami, J; Taylor, WR; Garovic, VD
MLA Citation
Sparks, Matthew A., et al. “Severe Acute Respiratory Syndrome Coronavirus 2, COVID-19, and the Renin-Angiotensin System: Pressing Needs and Best Research Practices.Hypertension, vol. 76, no. 5, Nov. 2020, pp. 1350–67. Pubmed, doi:10.1161/HYPERTENSIONAHA.120.15948.
URI
https://scholars.duke.edu/individual/pub1461681
PMID
32981369
Source
pubmed
Published In
Hypertension
Volume
76
Published Date
Start Page
1350
End Page
1367
DOI
10.1161/HYPERTENSIONAHA.120.15948