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，脂肪毒性和近端小管细胞死亡之间的关系。我们已经表明，使用配体的PPAR激活，或通过使用转基因小鼠在近端小管中提高PPAR的表达，可以使肾脏再灌注损伤（IRI）和肾毒性的顺铂模型改善肾脏功能。我们的初步研究表明，与野生型小鼠相比，在患有单侧缺血和单侧输尿管障碍物（UUO）的PPAR TG小鼠中，近端小管细胞死亡和间质纤维化的降低显着降低。我们的中心假设预测，近端小管和周围PPAR PPAR固定的肾小管炎症和肾纤维化的表达和活性增加，这是从急性到慢性肾脏疾病（CKD）进展的标志。具体目的1是确定增加近端小管（PT）-PPAR是否会干扰微管纤维纤维化。我们假设近端小管PPAR的表达增加会减弱肾纤维化。我们将使用野生型，遗传缺陷的PPAR小鼠，PPAR转基因小鼠和两种肾纤维化的动物模型来确定脂肪酸氧化增加，脂蛋白脂肪酶活性是否增加，自噬增加有助于脂肪毒性降低，并防止肾纤维化模型中近端肾小管细胞死亡。具体目的2是确定周细胞PPAR会影响周细胞到肌纤维细胞过渡的细胞机制。 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周细胞向肌纤维细胞的过渡。总而言之，这些研究将进一步提高我们对周细胞代谢和功能的了解，这应该提供其他治疗靶标，以防止AKI向CKD的发展。