The objective of this proposal is to study the role and signaling mechanisms by which the kallikreinkinin system (KKS) protects against salt-induced nephrosclerosis. The long-term goal is to develop novel therapeutic targets in the treatment and prevention of chronic renal disease and end-stage renal failure. Renal kallikrein levels are markedly reduced in humans and animal models with renal disease. By linkage analysis, we showed an association of a promoter polymorphic allele in the human tissue kallikrein gene with salt-induced hypertension and end-stage renal failure, as well as with blood pressure responses to changes in dietary sodium restriction. These findings implicate an important role of the KKS in salt-sensitive hypertension and renal function. Indeed, our preliminary studies show that elevated kallikrein/kinin levels (following kallikrein gene transfer) results in suppression of salt-induced inflammatory cell infiltration, glomerular enlargement, apoptosis, cell proliferation and collagen content in Dahl salt-sensitive (DS) rats. These protective effects were accompanied by increased nitric oxide (NO) levels and reduced oxidative stress and TGF-beta expression. Based on these findings, we hypothesize that the KKS through NO formation prevents and reverses salt-induced nephrosclerosis through inhibition of oxidative stress-induced signaling pathways. The following Specific Aims will be pursued to determine the signaling mechanisms that mediate the protective effects of the KKS in: 1) interstitial inflammation, 2) apoptosis, 3) proliferation and hypertrophy and 4) extracellular matrix accumulation leading to fibrosis. The signaling mechanisms may involve MCP-1, VCAM-1, ICAM-1, NF-kappaB, TGF-beta, MAPK, PA/MMP, PI3-kinase/Akt and p21/p27kip1. Enhanced kallikrein levels will be achieved by kallikrein gene delivery and kallikrein protein infusion into a salt-dependent hypertensive rat model. Cellular signaling pathways will be dissected in cultured endothelial and renal cells using specific inhibitors, neutralizing antibodies, dominant-negative DNA constructs, and small interference RNA. These studies should provide novel and in-depth information regarding the role of kallikrein/kinin in prevention and reversal of inflammation, apoptosis, proliferation, hypertrophy, and fibrosis that contribute to salt-induced nephrosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK066350-03
Application #
7084650
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Flessner, Michael Francis
Project Start
2004-07-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
3
Fiscal Year
2006
Total Cost
$282,287
Indirect Cost
Name
Medical University of South Carolina
Department
Biochemistry
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Gao, Lin; Chao, Lee; Chao, Julie (2010) A novel signaling pathway of tissue kallikrein in promoting keratinocyte migration: activation of proteinase-activated receptor 1 and epidermal growth factor receptor. Exp Cell Res 316:376-89
Gao, Lin; Smith, Robert S; Chen, Li-Mei et al. (2010) Tissue kallikrein promotes prostate cancer cell migration and invasion via a protease-activated receptor-1-dependent signaling pathway. Biol Chem 391:803-12
Liu, Yuying; Bledsoe, Grant; Hagiwara, Makato et al. (2010) Blockade of endogenous tissue kallikrein aggravates renal injury by enhancing oxidative stress and inhibiting matrix degradation. Am J Physiol Renal Physiol 298:F1033-40
Smith Jr, Robert S; Gao, Lin; Bledsoe, Grant et al. (2009) Intermedin is a new angiogenic growth factor. Am J Physiol Heart Circ Physiol 297:H1040-7
Yao, Yu-Yu; Yin, Hang; Shen, Bo et al. (2008) Tissue kallikrein promotes neovascularization and improves cardiac function by the Akt-glycogen synthase kinase-3beta pathway. Cardiovasc Res 80:354-64
Chao, Julie; Yin, Hang; Gao, Lin et al. (2008) Tissue kallikrein elicits cardioprotection by direct kinin b2 receptor activation independent of kinin formation. Hypertension 52:715-20
Hagiwara, Makoto; Shen, Bo; Chao, Lee et al. (2008) Kallikrein-modified mesenchymal stem cell implantation provides enhanced protection against acute ischemic kidney injury by inhibiting apoptosis and inflammation. Hum Gene Ther 19:807-19
Yin, Hang; Chao, Lee; Chao, Julie (2008) Nitric oxide mediates cardiac protection of tissue kallikrein by reducing inflammation and ventricular remodeling after myocardial ischemia/reperfusion. Life Sci 82:156-65
Bledsoe, Grant; Shen, Bo; Yao, Yu-Yu et al. (2008) Role of tissue kallikrein in prevention and recovery of gentamicin-induced renal injury. Toxicol Sci 102:433-43
Hagiwara, Makoto; Bledsoe, Grant; Yang, Zhi-Rong et al. (2008) Intermedin ameliorates vascular and renal injury by inhibition of oxidative stress. Am J Physiol Renal Physiol 295:F1735-43

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