The association of hypertension and kidney disease in diabetes is common and is associated with increased morbidity and mortality. Although inhibitors of the renin angiotensin system (RAS) are being used to treat hypertension and diabetic kidney disease, the number of individuals the mortality rate from cardiovascular disease continues to be high. All components of the RAS are present in the kidney in close proximity to the involved renal structures. Angiotensin II (Ang II) subtype-1 (AT1) receptors are localized in the renal blood vessels, glomeruli and tubules. Ang II subtype-2 (AT2) receptors are detected in adult rat kidney glomeruli, blood vessels and tubules. In the previous funding period of this application we demonstrated that there is a decrease in AT2 receptor expression and activity in presence of diabetes which contributes to development of renal disease through increased renal production of inflammatory and other vaso-active factors such as tumor necrosis factor-a (TNFa), transforming growth factor-?1 (TGF?1), endothelin-1 (ET- 1), thromboxan-?2 and local renal production of aldosterone. Recently, a novel prorenin receptor (MW 39KD) was discovered and localized in multiple organs including the kidney. The physiologic and pathologic functions of the prorenin receptors are unknown;much less it is interaction with the other components of the RAS. Our preliminary studies suggest that high glucose upregulates this receptor expression in the kidney leading to increased renal production of inflammatory factors. Independent of Ang II, it increases renal production of nuclear factor-?B, TNFa and interlukin-6 (IL-6). In addition we have preliminary data demonstrating presence of another novel form of the prorenin receptor (MW 66KD) which seems to have a major contribution to development of hypertension and kidney disease in presence of diabetes. This proposal will evaluate the hypothesis that in presence of diabetes, renal prorenin receptors mediate renal inflammation and matrix formation which contributes to development of hypertension and kidney disease. The proposed specific aims are:
AIM I : To test the hypothesis that glucose upregulates prorenin receptors expression through stimulation of protein kinase C -MAPK- cJun cascade.
AIM II : To test the hypothesis that in presence of hyperglycemia the cellular effects of the prorenin receptors are mediated via stimulation of ERK phosphorylation, NF?B, TNFa, IL-1, IL-6 and MCP-1, and is modulated by the interaction with the angiotensin AT1 and AT2 receptors.
AIM III : To test the hypothesis that in early stage diabetic nephropathy, prorenin receptor contributes to development of renal inflammation, matrix formation, proteinuria and hypertension. The proposed studies will help elucidate the mechanisms that are involved in development of hypertension and kidney disease and could lead to the development of new therapeutic modalities to prevent or slowdown the development of these diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL091535-10
Application #
8208167
Study Section
Special Emphasis Panel (ZRG1-CVS-D (02))
Program Officer
OH, Youngsuk
Project Start
2008-01-15
Project End
2013-06-30
Budget Start
2012-01-01
Budget End
2013-06-30
Support Year
10
Fiscal Year
2012
Total Cost
$374,963
Indirect Cost
$127,463
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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
Matavelli, Luis C; Huang, Jiqian; Siragy, Helmy M (2012) Combined aliskiren and amlodipine reduce albuminuria via reduction in renal inflammation in diabetic rats. J Cardiovasc Pharmacol 59:281-7
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

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