Diabetic nephropathy (DN) is the major single cause of end stage renal disease in the United States. DN is associated with vascular disease, including retinopathy, impaired wound healing and neuropathy. Although less recognized, increased glomerular neovascularization has also been observed in type 1 diabetes. However, at present it is not clear which molecular pathway/s control glomerular angiogenesis in diabetes. Cyclooxygenases (COX) 1 and 2 are key enzymes involved in the generation of prostaglandin E2 (PGE2). Notably, COX-2 is over-expressed in both renal cortex and medulla of diabetic mice. The observation that treatment of diabetic mice with COX-2 inhibitors reduces the expression of pro-angiogenesis molecules as well as albuminuria, strongly suggest a role for COX-derived prostanoids in DN. As i) increased COX expression is observed in diabetic kidneys, ii) PGE2 stimulates angiogenesis, iii) PGE2 increases endothelial permeability, and iv) the PGE2 EP4 receptor is highly expressed in glomeruli, we hypothesize that a functional prostaglandin dependent pathway is activated in diabetic kidney disease and promotes glomerular angiogenesis. To test this hypothesis we will assess 1) the contribution of COX-1 versus COX-2 derived prostanoids to the progression of neovascularization in mouse models of type I diabetes; 2) the role of a microsomal prostaglandin E2 synthase in the production of PGE2 and consequent glomerular neovascularization in type I diabetes and 3) the role of the glomerular endothelial and podocytes EP4 in the progression of diabetic. This study will enable us not only to define how COXs, PGE2 and its receptors alter glomerular microvascular angiogenesis in the setting of type 1 diabetes, but also to define whether preventing PGE2 synthesis and/or EP receptor activation might provide a specific therapeutic strategy to the treatment for altered angiogenesis in DN. This work will be a joint effort between Drs. Breyer and Pozzi. Dr. Breyer's group has been studying the roles of renal cyclooxygenase and PGE2 for over 15 years and has generated several of the transgenic mouse models used to study prostanoid function. His group also has substantial experience phenotyping mouse models of diabetic nephropathy. Dr. Pozzi studies the role of integrin (1(1, a major collagen binding receptor, in the control of endothelial cell biology and collagen homeostasis, two relevant aspects in DN. Recently she has examined the contribution of COX-2-derived PGE2 and its receptor EP4 in the control of tumor angiogenesis. Moreover, Drs. Pozzi and Breyer published in JBC an article on the role of COX-2 in the renal medullary interstitial cell survival. We believe the present proposal provides synergy between Dr. Pozzi's expertise in angiogenesis and Dr. Breyer's expertise in mouse models of diabetic nephropathy, and draws on their common interest in the prostanoid pathway in cell differentiation and survival

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK074359-03
Application #
7262465
Study Section
Special Emphasis Panel (ZDK1-GRB-4 (O1))
Program Officer
Rys-Sikora, Krystyna E
Project Start
2005-09-30
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
3
Fiscal Year
2007
Total Cost
$254,706
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Pozzi, Ambra; Voziyan, Paul A; Hudson, Billy G et al. (2009) Regulation of matrix synthesis, remodeling and accumulation in glomerulosclerosis. Curr Pharm Des 15:1318-33
Wang, Shizhen Emily; Xiang, Bin; Zent, Roy et al. (2009) Transforming growth factor beta induces clustering of HER2 and integrins by activating Src-focal adhesion kinase and receptor association to the cytoskeleton. Cancer Res 69:475-82
Zhang, Ming-Zhi; Xu, Jie; Yao, Bing et al. (2009) Inhibition of 11beta-hydroxysteroid dehydrogenase type II selectively blocks the tumor COX-2 pathway and suppresses colon carcinogenesis in mice and humans. J Clin Invest 119:876-85
Pozzi, Ambra; Zent, Roy; Chetyrkin, Sergei et al. (2009) Modification of collagen IV by glucose or methylglyoxal alters distinct mesangial cell functions. J Am Soc Nephrol 20:2119-25
Yang, Shiling; Wei, Shouzou; Pozzi, Ambra et al. (2009) The arachidonic acid epoxygenase is a component of the signaling mechanisms responsible for VEGF-stimulated angiogenesis. Arch Biochem Biophys 489:82-91
Pozzi, Ambra; Zent, Roy (2009) Regulation of endothelial cell functions by basement membrane- and arachidonic acid-derived products. Wiley Interdiscip Rev Syst Biol Med 1:254-272
Borza, Corina M; Borza, Dorin-Bogdan; Pedchenko, Vadim et al. (2008) Human podocytes adhere to the KRGDS motif of the alpha3alpha4alpha5 collagen IV network. J Am Soc Nephrol 19:677-84
Erdogan, Mete; Pozzi, Ambra; Bhowmick, Neil et al. (2008) Transforming growth factor-beta (TGF-beta) and TGF-beta-associated kinase 1 are required for R-Ras-mediated transformation of mammary epithelial cells. Cancer Res 68:6224-31
Macias-Perez, Ines M; Zent, Roy; Carmosino, Monica et al. (2008) Mouse EP3 alpha, beta, and gamma receptor variants reduce tumor cell proliferation and tumorigenesis in vivo. J Biol Chem 283:12538-45
Abair, Tristin D; Sundaramoorthy, Munirathinam; Chen, Dong et al. (2008) Cross-talk between integrins alpha1beta1 and alpha2beta1 in renal epithelial cells. Exp Cell Res 314:3593-604

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