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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。我们已经表明，激活的过氧化物酶体增殖物激活物使用配体，或通过增加表达的过氧化物酶体增殖物激活物在近端小管使用转基因小鼠改善肾功能的缺血再灌注损伤（IRI），顺铂模型的肾毒性。我们的初步研究表明，与野生型小鼠相比，在单侧缺血和单侧输尿管梗阻（UUO）的PPAR Tg小鼠中，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的表达和活性增加阻断了肾小管间质炎症和肾纤维化，这是从急性到慢性肾病（CKD）进展的标志。具体目的1是确定增加的近端小管（PT）-PPAR是否干扰肾小管间质纤维化。我们推测近曲小管过氧化物酶体增殖物激活受体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、PPAR转基因小鼠和两种肾纤维化动物模型，以确定增加的脂肪酸氧化、脂蛋白脂肪酶活性和增加的自噬是否有助于降低肾纤维化模型中的脂毒性并防止近端小管细胞死亡。具体目标2是确定周细胞过氧化物酶体增殖物激活受体影响周细胞向肌成纤维细胞转变的细胞机制。我们提出分离和培养小鼠肾周细胞，以1）确定PPAR过表达对周细胞向肌成纤维细胞转化的影响，2）确定PPAR介导的脂肪酸氧化增加、中性脂质积累减少和/或周细胞脂肪形成的变化是否在体外阻止周细胞向肌成纤维细胞转化，和3）确定PPAR缺乏对周细胞向肌成纤维细胞转变的作用。总之，这些研究将进一步推进我们对周细胞代谢和功能的了解，这将提供额外的治疗靶点，以防止阿基进展为CKD。