(Pro)renin receptor (PRR) is a newly discovered component of the renin-angiotensin system. Recent studies suggested interaction of this receptor with vacuolar H+ATPase (V-ATPase) and Wnt signaling pathways. However, the exact physiologicand pathologic functions of PRR are not established yet. Total deletion of PRR is lethal, and unavailability of conditional knockout or its specific blockers made it difficult to study this receptor. Our preliminary data demonstrated that renal PRR expression is increased in response to low sodium intake and renal artery clipping of 2-kidney-1-clip hypertension rat model (2K1C), and that PRR contributes to the regulation of expression of V-ATPase, Wnt3a (involving canonical-2-catenin signaling pathway) and Wnt7a (involving non-canonical pathway). Based on these data, it is likely that PRR is involved in development or progression of renal disease. The long-term goal of our research program to elucidate the in vitro and in vivo novel mechanisms contributing to the regulation of PRR expression and function and evaluate the pathological significance of this receptor interaction with V-ATPase and Wnt signaling pathways in development of hypertension-induced renal injury. To achieve this goal, we will utilize a rationale and novel integrated approaches, consisting of in vitro and in vivo studies localized to the kidney including state-of-the-art cellular and molecular techniques, siRNA and shRNA, Laser Scanning Confocal FRET microscopy and in vivo microdialysis to more rigorously test the proposed ideas. Based on our preliminary data, the central hypothesis of this proposal is that angiotensin AT1 (AT1R) and AT2 (AT2R) receptors regulate the expression of PRR via their signaling pathways and that PRR enhances the expression and function of V-ATPase, Wnt3a and Wnt7a to induce renal inflammation and fibrosis in 2K1C hypertension rat model. We will pursue the following specific aims:
Aim 1. To test the hypothesis that PRR expression and activity are upregulated via AT1R-mitogen-activated protein kinase, nuclear factor-:B (NF:B), and activator protein-1 (AP-1) signaling pathways.
Aim 2. To test the hypothesis that PRR expression and activity are downregulated via AT2R-nitric oxide (NO)-cGMP-protein kinase G (PKG) signaling pathway and through physical interaction (dimerization) between these two receptors.
Aim 3. To test the hypothesis that V-ATPase mediates PRR induced renal injury in 2K1C hypertension rat model.
Aim 4. To test the hypothesis that in the kidney, PRR regulates Wnt3a and Wnt7a expressions and mediates their signaling pathways leading to inflammation and fibrosis in 2K1C hypertension rat model. These studies are expected to identify novel pathophysiologic mechanisms related to PRR and its contribution to renal injury and could lead to development of new therapeutic strategies in treating hypertension-induced renal disease.

Public Health Relevance

Despite the availability of numerous drugs to treat hypertension-induced renal disease, the success rate is less than optimal. This application will identify novel mechanisms involving (Pro)renin receptor in development of hypertension-induced renal injury. Elucidation of these mechanisms would allow the development of new therapeutic tools and strategies to treat renal complications associated with hypertension.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK078757-08
Application #
8662750
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Ketchum, Christian J
Project Start
2007-07-01
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Quadri, Syed; Siragy, Helmy M (2016) (Pro)renin receptor contributes to regulation of renal epithelial sodium channel. J Hypertens 34:486-94; discussion 494
Quadri, Syed S; Culver, Silas A; Li, Caixia et al. (2016) Interaction of the renin angiotensin and cox systems in the kidney. Front Biosci (Schol Ed) 8:215-26
Ramkumar, Nirupama; Stuart, Deborah; Calquin, Matias et al. (2015) Nephron-specific deletion of the prorenin receptor causes a urine concentration defect. Am J Physiol Renal Physiol 309:F48-56
Matavelli, Luis C; Siragy, Helmy M (2015) AT2 receptor activities and pathophysiological implications. J Cardiovasc Pharmacol 65:226-32
Matavelli, Luis C; Zatz, Roberto; Siragy, Helmy M (2015) A nonpeptide angiotensin II type 2 receptor agonist prevents renal inflammation in early diabetes. J Cardiovasc Pharmacol 65:371-6
Li, Caixia; Culver, Silas A; Quadri, Syed et al. (2015) High-fat diet amplifies renal renin angiotensin system expression, blood pressure elevation, and renal dysfunction caused by Ceacam1 null deletion. Am J Physiol Endocrinol Metab 309:E802-10
Li, Caixia; Siragy, Helmy M (2015) (Pro)renin receptor regulates autophagy and apoptosis in podocytes exposed to high glucose. Am J Physiol Endocrinol Metab 309:E302-10
Abadir, Peter M; Siragy, Helmy M (2015) Angiotensin type 1 receptor mediates renal production and conversion of prostaglandins E2 to F2α in conscious diabetic rats. J Renin Angiotensin Aldosterone Syst 16:774-9
Li, Caixia; Siragy, Helmy M (2014) High glucose induces podocyte injury via enhanced (pro)renin receptor-Wnt-β-catenin-snail signaling pathway. PLoS One 9:e89233
Quadri, Syed; Siragy, Helmy M (2014) Regulation of (pro)renin receptor expression in mIMCD via the GSK-3β-NFAT5-SIRT-1 signaling pathway. Am J Physiol Renal Physiol 307:F593-600

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