The renin-angiotensin system (RAAS) is a major physiological regulator of body fluid volume, electrolyte balance, and arterial pressure. Majority of the biological actions of angiotensin II (Ang II), the principal effector peptide of the RAAS, are attributed to its action at the Ang II subtype-1 receptor (AT1R). Ang II also stimulates its subtype-2 receptor (AT2R) to mainly produce vasodilation and inhibition of cell hypertrophy and proliferation. However, the functions of the AT2R are not completely unknown. Recently, a new receptor that binds to renin/prorenin receptor was discovered and termed renin/prorenin receptor (RR). The role of the RR in physiology and pathology is unknown. Preliminary data from our laboratory'and others suggested that RR mediates specific effects independent of Ang II. Stimulation of RR seems to induce rapid activation of mitogen-activated protein kinases p44/p42. Currently, the exact distribution, regulation and functions of the RRs in the kidney are unknown. Preliminary data presented in this application suggest that renin receptor is present in the renal glomeruli and tubules and is regulated by salt intake. In addition, there are preliminary data to suggest an interaction between, AT1R or AT2R and the RR. This proposal will expand on these preliminary studies and will address the following questions: 1) What are the factors that regulate the expression of the RR? 2) What are the consequences (functions) resulting from RR stimulation? 3) Is there a cross talk between the AT1R or the AT2R and RR? 4) What is the role of RR in renovascular hypertension? The main hypothesis of this proposal is that: The renal RR contributes to development of renal inflammation and fibrosis.
The specific aims for this proposal are:
AIM 1 : To test the hypothesis that sodium intake regulates RR expression and activity.
AIM II : To test the hypothesis that AT1R or AT2R regulate RR expression and activity.
AIM III : To test the hypothesis that RR expression and activity is increased in renovascular hypertension rat model. Information gained from this proposal will lead to increased understanding of the pathophysiology of hypertension and development of novel therapies for its management.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK078757-04
Application #
7813934
Study Section
Special Emphasis Panel (ZRG1-CVS-B (02))
Program Officer
Ketchum, Christian J
Project Start
2007-07-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
4
Fiscal Year
2010
Total Cost
$301,320
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Quadri, Syed S; Culver, Silas; Siragy, Helmy M (2017) Prorenin receptor mediates inflammation in renal ischemia. Clin Exp Pharmacol Physiol :
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
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
Abadir, Peter M; Siragy, Helmy M (2015) Angiotensin type 1 receptor mediates renal production and conversion of prostaglandins E2 to F2? in conscious diabetic rats. J Renin Angiotensin Aldosterone Syst 16:774-9
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
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
Matavelli, Luis C; Siragy, Helmy M (2015) AT2 receptor activities and pathophysiological implications. J Cardiovasc Pharmacol 65:226-32
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
Li, Caixia; Siragy, Helmy M (2014) High glucose induces podocyte injury via enhanced (pro)renin receptor-Wnt-?-catenin-snail signaling pathway. PLoS One 9:e89233

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