Role of PPARalpha in acute kidney injury

描述（由申请人提供）：我们建议研究底物氧化，脂肪毒性和近端小管细胞死亡之间的关系。我们已经证明，通过配体激活pparα，或通过增加转基因小鼠近端小管中pparα的表达，可以改善缺血再灌注损伤（IRI）和顺铂肾毒性模型中的肾功能。我们的初步研究表明，与野生型小鼠相比，单侧缺血和单侧输尿管梗阻（UUO）的ppar - Tg小鼠近端小管细胞死亡和间质纤维化显著减少。我们的中心假设预测，近端小管和周细胞ppar α表达和活性的增加可以阻断小管间质炎症和肾纤维化，这是糖尿病的一个标志

DESCRIPTION (provided by applicant): We propose to examine the relationship between substrate oxidation, lipotoxicity and proximal tubule cell death. We have shown that activation of PPARalpha using a ligand, or by increased expression of PPARalpha in the proximal tubule using transgenic mice ameliorates kidney function in the ischemia reperfusion injury (IRI), and cisplatin model of nephrotoxicity. Our preliminary studies demonstrate a significant reduction in proximal tubule cell death and reduced interstitial fibrosis in PPARalpha Tg mice subjected to both unilateral ischemia and Unilateral Ureteral Obstruction (UUO), when compared to wild type mice. Our central hypothesis predicts that increased expression and activity of proximal tubule and pericyte PPARalpha interdict tubulo-interstitial inflammation and renal fibrosis, a hallmark of the progression from Acute to Chronic Kidney Disease (CKD). Specific Aim 1. To determine whether increased proximal tubule (PT)-PPARalpha interdicts with tubulo-interstitial fibrosis. We hypothesize that increased expression of proximal tubule PPARalpha attenuates renal fibrosis. We will use wild type, genetically deficient PPARalpha mice, and PPARalpha transgenic mice and two animal models of renal fibrosis to determine if increased fatty acid oxidation, lipoprotein lipase activity, and increased autophagy contribute to reduced lipotoxicity and prevent proximal tubule cell death in models of renal fibrosis. Specific Aim 2. To examine the mechanisms by which increased proximal tubule (PT)-PPARalpha reduces renal fibrosis. We will address several independent mechanisms by which PPARalpha expression could reduce renal fibrosis: 1) by changing macrophage phenotype in UUO mice 2) by increasing structural repair after reversal of UUO and 3) by reducing myofibroblast proliferation in renal interstitium. Specific Aim 3. To determine cellular mechanisms by which PPARalpha reduces renal fibrosis in mouse kidney pericytes. Our preliminary studies show that PPARalpha expression as well as expression of fatty acid oxidation genes are significantly reduced in pericytes isolated from UUO mice. We propose to isolate and culture mouse kidney pericytes from wild type mice 1) to determine the effects of PPARalpha overexpression on pericyte to myofibroblasts transition in vitro, 2) to determine whether PPARalpha mediated increase in fatty acid oxidation, reduced neutral lipid accumulation, and changes on adipogenesis contribute to the transition from pericytes to myofibroblasts in vitro, 3) to determine the role of increased cellular autophagy on pericyte to myofibroblasts transition, and 4) to determine the role of PPARalpha deficiency on primary pericytes transition to myofibroblasts. Altogether these studies will further advance our knowledge of pericyte metabolism and function and should provide additional therapeutic targets to manage chronic kidney disease.