Hypertension is a common and morbid complication of obesity. The pathophysiologic mechanisms involved in obesity-induced hypertension are not well elucidated. In this application we propose that (Pro)renin receptor (PRR), a newly discovered receptor, plays a major role in the development of obesity associated hypertension. Recent studies confirmed presence of this receptor in adipose tissue and kidneys. The lack of PRR specific antagonists and the lethality of its total deletion, made it difficult to study this receptor. Currently, the contribution of PRR to development of obesity-induced hypertension is unknown. In order to study PRR in adipose tissue and the kidney, this proposal will utilize two novel mouse models namely the inducible adipocyte specific PRR knockout mouse and the inducible nephron specific PRR knockout mouse. Our preliminary data demonstrated that obese mice developed hypertension with increased PRR expression and production of proinflammatory cytokines in adipose tissue and kidneys. These data also suggested that PRR regulates ?ENaC expression in the kidney. Based on these data, we propose that PRR contributes to development of obesity-induced hypertension by enhancing sodium retention. The long-term goal of our research program is to elucidate the novel mechanisms contributing to the regulation of PRR expression and function and evaluate its interaction with proinflammatory cytokines, angiotensin subtype AT1 receptor (AT1R), and ?ENaC in development of obesity-induced inflammation and hypertension. To achieve this goal, we will utilize a rationale and novel integrated approaches, including in vitro state-of-the-art cellular and molecular techniques, in vivo studies utilizing two novel inducible tissue specific PRR knockout mouse models, Laser Scanning Confocal FRET microscopy and in vivo microdialysis, to rigorously test the proposed hypothesis. Based on our preliminary data, the central hypothesis of this proposal is that PRR contributes to the development of obesity-induced hypertension via enhancing adipose tissue and kidney inflammation and PRR-AT1R dimer formation, leading to increased renal ?ENaC activity and sodium retention. We will pursue the following integrated specific aims:
Specific Aim I : To test the hypothesis that adipocyte PRR contributes to the development of obesity-induced hypertension via enhancing adipocyte IL-1, IL-6, TNF?-renal ?ENaC pathway.
Specific Aim II : To test the hypothesis that the nephron PRR contributes to the development of obesity- induced hypertension via enhancing PI3K-AKT-mTOR-SGK1-Nedd4-2-?-ENaC pathway.
Specific Aim III : To test the hypothesis that PRR forms a heterodimer with angiotensin AT1R to enhance development of obesity-induced hypertension, via ERK-NF?B-proinflammatory cytokines-?ENaC pathway. These studies will identify novel pathophysiologic mechanisms related to obesity-induced hypertension and could lead to the development of new therapeutic strategies in treating this common problem.
Hypertension is a common and morbid complication of obesity. It is estimated that about 32% of Americans currently obese. This application will identify novel mechanisms involving (Pro)renin receptor in development of obesity induced hypertension. Elucidation of these mechanisms would allow the development of new therapeutic tools and strategies to treat this common medical problem.
| Quadri, Syed S; Culver, Silas; Siragy, Helmy M (2018) Prorenin receptor mediates inflammation in renal ischemia. Clin Exp Pharmacol Physiol 45:133-139 |
