PPARGAMMA AND AII IN GLOMERULOSCLEROSIS

PPARGAMMA 和 AII 在肾小球硬化症中的作用

• 批准号: 6142983
• 负责人: Willa A Hsueh
• 金额: $ 5.51万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6142983
• 关键词: collagenase; diabetes mellitus; diabetic nephropathy; enzyme inhibitors; gene targeting; genetically modified animals; glomerulosclerosis; kidney cell; laboratory mouse; laboratory rat; losartan; mesangium; mitogen activated protein kinase; plasminogen activator inhibitors; receptor expression; renal glomerulus; retinoate; streptozotocin; tissue /cell culture

An imbalance whereby glomerular extracellular matrix (ECM) production is increased and degradation is decreased leads to a relative and absolute increase in ECM volume in the diabetic mesangium. This crucical alteration impairs glomerular filtering capacity and results in glomerulosclerosis and end-stage renal disease. Plasminogen activator inhibitor-1 (PAI-1) is produced by mesangial cells in response to growth factor stimulation, is increased in glomeruli of diabetic animals and humans and, importantly, is a major factor preventing the degradation of mesangial ECM by inhibiting the activation of plasmin and metalloproteinases (MMP). We identified the presence of novel steroid receptors, which function as heterodimers, peroxisomal proliferator-activated receptors, PPARgamma, and retinoic acid receptor, RXRalpha, in cultured mesangial cells and in glomerular cores. PPARgamma activation substantially decreased PAI-1 expression, which likely resulted from inhibition of the nuclear effects of the mitogen activated protein kinase (MAPK) pathway. We hypothesize that PPARgamma activation will attenuate the development and progression of diabetic glomerulopathy. Specific aims include: 1) Demonstrate that administration of PPARgamma ligands or novel MAPK inhibitors will prevent glomerular structural changes in rats given streptozotocin (STZ). This aim will determine whether PPARgamma activation affects the glomerulus in vivo, which would support our preliminary data. 2) Define the role of PAI-1 in mediating glomerulosclerosis. This aim will examine changes in the PAI-1 system and MMP in cultured cells and in glomeruli of animal models treated with PPARgamma ligands. Importantly, PAI-1 knockout mice will be given STZ and the development of nephropathy will be compared with that of wild type controls. 3) Investigate the regulation and function of PPARgamma in cultured mesangial cells. This aim will assess whether growth factors or the diabetic milieu alters PPARgamma or RXRalpha expression and examines the effects of receptor activation on mesangial cell growth, apoptosis, ECM and integrin expression. The major contribution of this proposal will be to develop a readily applicable, potential therapeutic approach to inhibit or attenuate the development of diabetic nephropathy by using PPARgamma ligands and to elucidate the mechanism by which activation of these receptors impact on critical cellular signaling pathways.

肾小球细胞外基质（ECM）产生增加而降解减少的不平衡导致糖尿病系膜中ECM体积的相对和绝对增加。 这一关键性改变损害肾小球滤过能力，导致肾小球硬化和终末期肾病。 纤溶酶原激活物抑制剂-1（派-1）由系膜细胞响应于生长因子刺激而产生，在糖尿病动物和人类的肾小球中增加，并且重要的是，其是通过抑制纤溶酶和金属蛋白酶（MMP）的活化来防止系膜ECM降解的主要因子。 我们确定了新的类固醇受体的存在，其功能异源二聚体，过氧化物酶体增殖物激活受体，PPARgamma和视黄酸受体，RXR α，在培养的系膜细胞和肾小球核心。 PPARgamma的激活显著降低派-1的表达，这可能是由于抑制了丝裂原活化蛋白激酶（MAPK）通路的核效应。我们假设PPARgamma激活将减弱糖尿病肾小球病变的发展和进展。 具体目标包括：1）证明给予PPARgamma配体或新型MAPK抑制剂将防止给予链脲佐菌素（STZ）的大鼠的肾小球结构变化。 这一目标将确定是否PPARgamma激活影响肾小球在体内，这将支持我们的初步数据。 2)明确派-1在肾小球硬化中的作用。 该目的将检测培养细胞和用PPARgamma配体处理的动物模型肾小球中派-1系统和MMP的变化。 重要的是，派-1敲除小鼠将被给予STZ，并将肾病的发展与野生型对照进行比较。 3)探讨体外培养的肾小球系膜细胞中PPAR γ的表达调控及其功能。 这一目的将评估生长因子或糖尿病环境是否改变PPARgamma或RXR alpha表达，并检查受体活化对系膜细胞生长、凋亡、ECM和整合素表达的影响。 该提案的主要贡献将是开发一种易于应用的潜在治疗方法，通过使用PPARgamma配体来抑制或减轻糖尿病肾病的发展，并阐明这些受体的激活影响关键细胞信号传导途径的机制。