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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK038226-27
Application #
8521247
Study Section
Special Emphasis Panel (ZDK1-GRB-S)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
27
Fiscal Year
2013
Total Cost
$176,466
Indirect Cost
$63,149
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Gangadhariah, Mahesha H; Luther, James M; Garcia, Victor et al. (2015) Hypertension is a major contributor to 20-hydroxyeicosatetraenoic acid-mediated kidney injury in diabetic nephropathy. J Am Soc Nephrol 26:597-610
Zeng, Fenghua; Miyazawa, Tomoki; Kloepfer, Lance A et al. (2014) Deletion of ErbB4 accelerates polycystic kidney disease progression in cpk mice. Kidney Int 86:538-47
Luther, James M; Byrne, Loretta M; Yu, Chang et al. (2014) Dietary sodium restriction decreases insulin secretion without affecting insulin sensitivity in humans. J Clin Endocrinol Metab 99:E1895-902
Bajpai, Prachi; Srinivasan, Satish; Ghosh, Jyotirmoy et al. (2014) Targeting of splice variants of human cytochrome P450 2C8 (CYP2C8) to mitochondria and their role in arachidonic acid metabolism and respiratory dysfunction. J Biol Chem 289:29614-30
Hye Khan, Md Abdul; Pavlov, Tengis S; Christain, Sarah V et al. (2014) Epoxyeicosatrienoic acid analogue lowers blood pressure through vasodilation and sodium channel inhibition. Clin Sci (Lond) 127:463-74
Keller, Julia; Ellieva, Alexandra; Ma, Dengke K et al. (2014) CYP-13A12 of the nematode Caenorhabditis elegans is a PUFA-epoxygenase involved in behavioural response to reoxygenation. Biochem J 464:61-71
Chen, Li; Ackerman, Rachel; Saleh, Mohamed et al. (2014) 20-HETE regulates the angiogenic functions of human endothelial progenitor cells and contributes to angiogenesis in vivo. J Pharmacol Exp Ther 348:442-51
Wang, Wen-Hui; Zhang, Chengbiao; Lin, Dao-Hong et al. (2014) Cyp2c44 epoxygenase in the collecting duct is essential for the high K+ intake-induced antihypertensive effect. Am J Physiol Renal Physiol 307:F453-60
Nithipatikom, Kasem; Endsley, Michael P; Pfeiffer, Adam W et al. (2014) A novel activity of microsomal epoxide hydrolase: metabolism of the endocannabinoid 2-arachidonoylglycerol. J Lipid Res 55:2093-102
Falck, John R; Koduru, Sreenivasulu Reddy; Mohapatra, Seetaram et al. (2014) 14,15-Epoxyeicosa-5,8,11-trienoic Acid (14,15-EET) surrogates: carboxylate modifications. J Med Chem 57:6965-72

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