Role of PPARa on renal fibrosis

PPARa 对肾纤维化的作用

基本信息

批准号：
8635589
负责人：
DIDIER PORTILLA
金额：
--
依托单位：
CENTRAL ARKANSAS VETERANS HLTHCARE SYS
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2016-03-31
项目状态：
已结题

项目摘要

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 PPAR using a ligand, or by increased expression of PPAR 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 PPAR 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 PPAR interdict tubulo-interstitial inflammation and renal fibrosis, a hallmark of the progression from Acute to Chronic Kidney Disease (CKD). Specific Aim 1 is to determine whether increased proximal tubule (PT)-PPAR interferes with tubulo-interstitial fibrosis. We hypothesize that increased expression of proximal tubule PPAR attenuates renal fibrosis. We will use wild type, genetically deficient PPAR mice, and PPAR 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 is to determine cellular mechanisms by which pericyte PPAR influences pericyte to myofibroblast transition. We propose to isolate and culture mouse kidney pericytes in order to 1) determine the effects of PPAR overexpression on the pericyte-to-myofibroblast transition, 2) determine whether the PPAR-mediated increase in fatty acid oxidation, reduced neutral lipid accumulation, and/or changes to pericyte adipogenesis prevent the pericyte conversion to myofibroblasts in vitro, and 3) to determine the role of PPAR deficiency on the transition of pericytes to myofibroblasts. Altogether, these studies will further advance our knowledge of pericyte metabolism and function, which should provide additional therapeutic targets to prevent the progression of AKI to CKD.

描述（由申请人提供）：我们建议检查底物氧化、脂毒性和近端小管细胞死亡之间的关系。我们已经证明，使用配体激活 PPAR，或使用转基因小鼠增加近曲小管中 PPAR 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，遭受单侧缺血和单侧输尿管梗阻 (UUO) 的 PPAR Tg 小鼠的近端小管细胞死亡显着减少，间质纤维化减少。我们的中心假设预测，近端肾小管和周细胞 PPAR 的表达和活性增加可阻止肾小管间质炎症和肾纤维化，这是从急性肾病进展为慢性肾病 (CKD) 的标志。具体目标 1 是确定近端小管 (PT)-PPAR 增加是否会干扰肾小管间质纤维化。我们假设近曲小管 PPAR 表达增加可减轻肾纤维化。我们将使用野生型、遗传缺陷型 PPAR 小鼠和 PPAR 转基因小鼠以及两种肾纤维化动物模型来确定脂肪酸氧化增加、脂蛋白脂肪酶活性增加和自噬增加是否有助于降低模型中的脂毒性并防止近曲小管细胞死亡。肾纤维化。具体目标 2 是确定周细胞 PPAR 影响周细胞向肌成纤维细胞转变的细胞机制。我们建议分离和培养小鼠肾周细胞，以便 1) 确定 PPAR 过表达对周细胞向肌成纤维细胞转变的影响，2) 确定 PPAR 是否介导脂肪酸氧化增加、中性脂质积累减少和/或周细胞脂肪生成的改变阻止周细胞在体外转化为肌成纤维细胞，并且3)确定PPAR缺乏对周细胞向肌成纤维细胞转化的作用肌成纤维细胞。总而言之，这些研究将进一步增进我们对周细胞代谢和功能的了解，这应该提供额外的治疗靶点，以防止 AKI 进展为 CKD。