Role of Cyclooxygenase stimulated Neovascularization in Diabetic Nephropathy

Summary

Principal Investigator: Chuan Ming Hao
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2005-09-30 - 2009-07-31
more information: NIH RePORT

Top Publications

  1. ncbi Diabetic nephropathy: leveraging mouse genetics
    Matthew D Breyer
    Division of Nephrology, Department of Medicine and Department of Molecular Physiology and Biophysics, Vanderbilt University, and Veterans Administration Medical Center, Nashville, Tennessee 3723, USA
    Curr Opin Nephrol Hypertens 15:227-32. 2006
  2. ncbi Long-term treatment of glucagon-like peptide-1 analog exendin-4 ameliorates diabetic nephropathy through improving metabolic anomalies in db/db mice
    Cheol Whee Park
    Division of Nephrology, Department of Internal Medicine, The Catholic University of Korea, 62 Yoido dong, Youngdungpo Ku, Seoul, Korea 150 713
    J Am Soc Nephrol 18:1227-38. 2007
  3. ncbi Prostaglandin E2-EP4 receptor promotes endothelial cell migration via ERK activation and angiogenesis in vivo
    Reena Rao
    Department of Medicine, Division of Nephrology, Vanderbilt University, Nashville, Tennessee 37232, USA
    J Biol Chem 282:16959-68. 2007
  4. pmc Effect of selective cyclooxygenase-2 (COX-2) inhibitor treatment on glucose-stimulated insulin secretion in C57BL/6 mice
    Hiroki Fujita
    Division of Endocrinology, Metabolism and Geriatric Medicine, Akita University School of Medicine, 1 1 1 Hondo, Akita 010 8543, Japan
    Biochem Biophys Res Commun 363:37-43. 2007
  5. pmc Sirt1 activation protects the mouse renal medulla from oxidative injury
    Wenjuan He
    Nephrology Division, Vanderbilt University Medical Center School of Medicine, Nashville, Tennessee 37232, USA
    J Clin Invest 120:1056-68. 2010
  6. pmc Renal function, bisphenol A, and alkylphenols: results from the National Health and Nutrition Examination Survey (NHANES 2003-2006)
    Li You
    Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
    Environ Health Perspect 119:527-33. 2011

Detail Information

Publications6

  1. ncbi Diabetic nephropathy: leveraging mouse genetics
    Matthew D Breyer
    Division of Nephrology, Department of Medicine and Department of Molecular Physiology and Biophysics, Vanderbilt University, and Veterans Administration Medical Center, Nashville, Tennessee 3723, USA
    Curr Opin Nephrol Hypertens 15:227-32. 2006
    ..Advances in mouse genetics have made this species particularly useful as a model for human disease. This review will summarize recent advances regarding the pathogenesis of diabetic nephropathy discovered in mice...
  2. ncbi Long-term treatment of glucagon-like peptide-1 analog exendin-4 ameliorates diabetic nephropathy through improving metabolic anomalies in db/db mice
    Cheol Whee Park
    Division of Nephrology, Department of Internal Medicine, The Catholic University of Korea, 62 Yoido dong, Youngdungpo Ku, Seoul, Korea 150 713
    J Am Soc Nephrol 18:1227-38. 2007
    ..These results suggest that exendin-4 could provide a therapeutic role in diabetic nephropathy that results from type 2 diabetes...
  3. ncbi Prostaglandin E2-EP4 receptor promotes endothelial cell migration via ERK activation and angiogenesis in vivo
    Reena Rao
    Department of Medicine, Division of Nephrology, Vanderbilt University, Nashville, Tennessee 37232, USA
    J Biol Chem 282:16959-68. 2007
    ..Finally, PGE(2), as well as PGE(1)-OH and ONO-AE1-329, also promoted angiogenesis in an in vivo sponge assay providing evidence that the EP4 receptor mediates de novo vascularization in vivo...
  4. pmc Effect of selective cyclooxygenase-2 (COX-2) inhibitor treatment on glucose-stimulated insulin secretion in C57BL/6 mice
    Hiroki Fujita
    Division of Endocrinology, Metabolism and Geriatric Medicine, Akita University School of Medicine, 1 1 1 Hondo, Akita 010 8543, Japan
    Biochem Biophys Res Commun 363:37-43. 2007
    ..These results collectively suggest that selective inhibition of COX-2 enhances glucose-stimulated insulin secretion through a reduction in PGE(2) production in pancreatic islets...
  5. pmc Sirt1 activation protects the mouse renal medulla from oxidative injury
    Wenjuan He
    Nephrology Division, Vanderbilt University Medical Center School of Medicine, Nashville, Tennessee 37232, USA
    J Clin Invest 120:1056-68. 2010
    ..We therefore suggest that Sirt1 provides a potential therapeutic target to minimize renal medullary cell damage following oxidative stress...
  6. pmc Renal function, bisphenol A, and alkylphenols: results from the National Health and Nutrition Examination Survey (NHANES 2003-2006)
    Li You
    Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
    Environ Health Perspect 119:527-33. 2011
    ..Urinary excretion of bisphenol A (BPA) and alkylphenols (APs) was used as a biomarker in most previous studies, but no study has investigated whether urinary excretion of these environmental phenols differed by renal function...