Diabefic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) in the United States. Recently, antidiabetic thiazolidinediones (TZDs) and hypolipidemic fibrates which specifically bind and activate peroxisome proliferator-activated receptor gamma (PPARgamma) and alpha (PPARalpha), respectively, have been found not only improve blood glucose and lipid levels but also slow the progression of DN in type 2 diabetes. Emerging evidence suggests that expression of the cytochrome P450 arachidonic acid (AA) monooxygenases (Cyp4a omega-hydroxylases and Cyp2c epoxygenases) is under control of PPARalpha and PPARgamma, and the Cyp4a-derived 20-HETE and the Cyp2c-derlved EETs may serve as engogenous ligands for both nuclear receptors. These data strongly suggests that the P450 AA monooxygenase metabolites 20-HETE and EETs may modulate PPAR function and play an important role in the pathogenesis of DN. The present proposal is designed to study the role of the P450 AA monooxygenases in the renoprotective effects of PPARalpha and PPARgamma agonists and to determine whether these enzymes and their metabolites are involved in the development of diabetic kidney disease. To achieve these aims we propose to: 1) characterize the role of Cyp4a and PPAR receptor interaction in DN. We will create a type 1 diabetic mouse (STZ-induced or Akita) and a type 2 diabetic mouse (db/db) deficient for Cyp4a10 and Cyp4a14 (Cyp4a10-/- and Cyp4a14-/-) or overexpressing Cyp4a12 (Cyp4a12 transgenic) to define the role of cyp4a enzymes in DN and the association between Gyp4a and the renoprotective effects of PPAR agonists;2) examine the role of Cyp2c44 and PPAR receptor interaction in DN. The effect of global Cyp2c44 delefion on the progression of DN will be examined in type 1 and type 2 diabetic mice. Type 1 and type 2 diabetic mice with glomerular Cyp2c44 gene deficiency will be made using the LoxP/Cre system and the progression of DN will be followed. The role of Cyp2c44 in the beneficial renal actions of PPAR agonists will also be determined. These studies should not only provide insights into the role of Cyp4a and Cyp2c in the pathogenesis of DN but also elucidate the possible underlying mechanisms by which EETs and HETEs affect DN.

Public Health Relevance

With the accelerating woridwide epidemic of type 2 diabetes, diabetic renal complications or diabetic nephropathy (DN) has become a serious public health concern. DN is the single most common cause of end stage renal disease (ESRD) in the US and more effective treatments are urgenfiy needed. Clarificafion of the role of the P450 enzymes in DN may lead to a novel strategy for the treatment of this kidney disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Vanderbilt University Medical Center
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