Data obtained in preliminary studies suggest that the renal kallikrein-kinin system (KKS) functions as a paracrine system, locally modulating renal function. The mechanisms by which these actions occur have not been fully elucidated. This proposal intends to examine the hypothesis that the renal actions of the KKS are mediated by endothelium-derived relaxing factor (EDRF), and eicosanoids. There are two specific aims that will be addressed in this proposal: (l) to examine the contribution of EDRF to the renal modulatory effects the renal KKS and (2) to examine whether kinin- induced changes in hemodynamics and excretory function are dependent on eicosanoid mechanisms. Bradykinin can stimulate the release of both EDRF and prostacyclin from endothelial cells and prostaglandin E2 from renal tubular epithelial cells. Within the kidney, EDRF and eicosanoids may function in a cell-to-cell manner to regulate renal hemodynamic and excretory function. The applicant has been involved in studies using an experimental model which functionally isolates the kidney in vivo in the conscious animal and can be employed for acute and chronic studies. Recently, the applicant developed a novel microdialysis method to sample renal interstitial fluid in the conscious dog and applied it to studies of the role of various hormones, including kinins in kidney function. The development of this microdialysis technique is essential to the examination of the hypothesis expressed in both Aims 1 and 2 which studies are to be conducted in conscious, chronically instrumented dogs. Specifically, the applicant proposes to localize the cellular targets of intrarenal kallikrein- kinin system by monitoring the levels of second messengers for EDRF (cyclic GMP) and eicosanoids (cyclic AMP). The proposed studies are related to the long term goal of increased understanding of the pathophysiology of fluid/electrolyte disorders and hypertension.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Modified Research Career Development Award (K04)
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Experimental Cardiovascular Sciences Study Section (ECS)
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University of Virginia
Internal Medicine/Medicine
Schools of Medicine
United States
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Siragy, Helmy M (2010) The angiotensin II type 2 receptor and the kidney. J Renin Angiotensin Aldosterone Syst 11:33-6
Siragy, Helmy M; Xue, Chun (2008) Local renal aldosterone production induces inflammation and matrix formation in kidneys of diabetic rats. Exp Physiol 93:817-24
Siragy, Helmy M; Huang, Jiqian (2008) Renal (pro)renin receptor upregulation in diabetic rats through enhanced angiotensin AT1 receptor and NADPH oxidase activity. Exp Physiol 93:709-14
Abdel-Rahman, Emaad M; Abadir, Peter M; Siragy, Helmy M (2008) Regulation of renal 12(S)-hydroxyeicosatetraenoic acid in diabetes by angiotensin AT1 and AT2 receptors. Am J Physiol Regul Integr Comp Physiol 295:R1473-8
Siragy, Helmy M (2007) Angiotensin AT1 and AT2 receptors--the battle for health and disease. Nephrol Dial Transplant 22:3128-30
Siragy, Helmy M; Inagami, Tadashi; Carey, Robert M (2007) NO and cGMP mediate angiotensin AT2 receptor-induced renal renin inhibition in young rats. Am J Physiol Regul Integr Comp Physiol 293:R1461-7
Abadir, Peter M; Periasamy, Ammasi; Carey, Robert M et al. (2006) Angiotensin II type 2 receptor-bradykinin B2 receptor functional heterodimerization. Hypertension 48:316-22
Xue, Chun; Siragy, Helmy M (2005) Local renal aldosterone system and its regulation by salt, diabetes, and angiotensin II type 1 receptor. Hypertension 46:584-90
Siragy, Helmy M; Xue, Chun; Abadir, Peter et al. (2005) Angiotensin subtype-2 receptors inhibit renin biosynthesis and angiotensin II formation. Hypertension 45:133-7
Awad, Alaa S; Webb, Randy L; Carey, Robert M et al. (2005) Increased renal production of angiotensin II and thromboxane B2 in conscious diabetic rats. Am J Hypertens 18:544-8

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