(Pro)renin receptor (PRR) is a newly discovered component of the renin-angiotensin system. The exact physiologic and pathologic functions of PRR are not established yet. Our preliminary studies in vitro and in vivo demonstrated that hyperglycemia increases PRR expression and activity, a process that is regulated by angiotensin AT1 receptor (AT1R), mainly via their heterodimerization. As a result of the interaction between AT1R and PRR there is upregulation of V-ATPase and Wnt3a expression and activity leading to renal inflammation fibrosis and albuminuria. In vivo intrarenal interstitia administration of PRR shRNA or Wnt3a shRNA reduced albuminuria, renal inflammation and morphologic changes associated with hyperglycemia. Based on these data, it is likely that PRR directly contributes to development of hyperglycemia-induced renal injury. The long-term goal of our research program is 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 AT1R, vacuolar-ATPase (V-ATPase) and Wnt3a, and lead to development of hyperglycemia- induced renal disease. To achieve this goal, we will utilize a rationale and novel integrated approaches, consisting of in vivo studies utilizing combined knockdown of renal PRR, V-ATPase or Wnt3a and renal interstitial microdialysis technique in conscious normoglycemic and hyperglycemic streptozotocin- induced diabetes rats. These studies will be complemented by state-of-the-art in vitro cellular and molecular techniques utilizing siRNA, shRNA, EMSA, ChIP assays, and Laser Scanning Confocal FRET microscopy to rigorously test the proposed hypothesis. Based on our recent observations and preliminary data, the central hypothesis of this proposal is that in presence of hyperglycemia, PRR activity is increased by dimerization with AT1R leading to enhanced expression and activity of V-ATPase and Wnt3a signaling pathways to induce renal inflammation, fibrosis and albuminuria. We will pursue the following specific aims:
Aim 1 : To test the hypothesis that hyperglycemia increases PRR expression and activity and its heterodimerization with AT1R, leading to renal inflammation, fibrosis and albuminuria.
Aim 2 : To test the hypothesis that hyperglycemia- enhanced PRR activity mediates renal injury by increasing the expression and activity of V-ATPase.
Aim 3 : To test the hypothesis that hyperglycemia-enhanced PRR activity contributes to renal injury via increased expression and activity of Wnt3a. These studies are expected to identify novel pathophysiologic mechanisms related to PRR and could lead to development of new therapeutic strategies for treating hyperglycemia-induced renal disease.

Public Health Relevance

Kidney disease is a common and morbid complication of diabetes and the leading cause of chronic kidney disease in the developed world. Approximately 40% of persons with diabetes develop kidney disease. It is associated with markedly increased risks of cardiovascular disease and death and higher health care costs. Diabetes-induced kidney disease accounts for nearly half of all incident cases of end-stage renal disease (ESRD) in the United States. Identifying novel pathophysiologic mechanisms induced by (Pro)renin receptor and its contribution to renal injury could lead to development of new therapeutic strategies for treating hyperglycemia-induced renal disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL091535-12
Application #
8707539
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
OH, Youngsuk
Project Start
2008-01-15
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
12
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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