(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.

National Institute of Health (NIH)
Research Project (R01)
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Hypertension and Microcirculation Study Section (HM)
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Ketchum, Christian J
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University of Virginia
Internal Medicine/Medicine
Schools of Medicine
United States
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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
Matavelli, Luis C; Siragy, Helmy M (2013) Reduction of aldosterone production improves renal oxidative stress and fibrosis in diabetic rats. J Cardiovasc Pharmacol 61:17-22
Huang, Jiqian; Ledford, Kelly J; Pitkin, William B et al. (2013) Targeted deletion of murine CEACAM 1 activates PI3K-Akt signaling and contributes to the expression of (Pro)renin receptor via CREB family and NF-*B transcription factors. Hypertension 62:317-23
Huang, Jiqian; Siragy, Helmy M (2012) Sodium depletion enhances renal expression of (pro)renin receptor via cyclic GMP-protein kinase G signaling pathway. Hypertension 59:317-23
Abadir, Peter M; Walston, Jeremy D; Carey, Robert M et al. (2011) Angiotensin II Type-2 receptors modulate inflammation through signal transducer and activator of transcription proteins 3 phosphorylation and TNFýý production. J Interferon Cytokine Res 31:471-4
Matavelli, Luis C; Huang, Jiqian; Siragy, Helmy M (2011) Angiotensin AT? receptor stimulation inhibits early renal inflammation in renovascular hypertension. Hypertension 57:308-13
Huang, Jiqian; Matavelli, Luis C; Siragy, Helmy M (2011) Renal (pro)renin receptor contributes to development of diabetic kidney disease through transforming growth factor-?1-connective tissue growth factor signalling cascade. Clin Exp Pharmacol Physiol 38:215-21
Siragy, Helmy M (2010) Improving vascular function in hypertension: potential benefits of combination therapy with amlodipine and renin-angiotensin-aldosterone system blockers. J Hypertens 28:2-8
Matavelli, Luis C; Huang, Jiqian; Siragy, Helmy M (2010) (Pro)renin receptor contributes to diabetic nephropathy by enhancing renal inflammation. Clin Exp Pharmacol Physiol 37:277-82
Siragy, Helmy M (2010) The angiotensin II type 2 receptor and the kidney. J Renin Angiotensin Aldosterone Syst 11:33-6

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