MECHANISMS OF RENAL LIPID RETENTION IN DIABETIC NEPHROPATHY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 肾病是糖尿病的主要并发症。肾脏脂质和脂蛋白的积聚加速了肾病的进展。导致肾脏脂蛋白积聚的机制尚不清楚。肾小球硬化是糖尿病肾病的特征性病变，系膜基质沉积增多，包括蛋白多糖。肾小球硬化的发生发展与动脉粥样硬化有许多共同之处。蛋白多糖由于具有结合和保留脂蛋白的能力，在动脉粥样硬化的形成过程中起着关键作用。我们最近发现，肾脏蛋白多糖表现出高的脂蛋白结合亲和力，并且转化生长因子-b增加了它们与低密度脂蛋白的结合亲和力。转化生长因子-β在糖尿病肾病的发生发展中起重要作用，糖尿病患者体内转化生长因子-β水平升高。转化生长因子-β刺激细胞外基质的合成，包括刺激小蛋白多糖二聚糖的合成。因此，糖尿病患者体内升高的转化生长因子-β可能刺激肾脏二聚糖的合成，从而介导肾脏脂质蓄积，加重糖尿病肾病的进展。这项拨款的总体目标是检验这一假说，即肾脏脂肪堆积是通过脂蛋白与肾脏蛋白多糖，特别是二聚糖的相互作用来调节的。为了确定肾脏脂质堆积是否通过蛋白多糖滞留低密度脂蛋白而介导，将在表达蛋白多糖结合缺陷低密度脂蛋白的小鼠和表达野生型低密度脂蛋白的小鼠之间进行糖尿病肾病的比较。为了确定双聚糖是否是蛋白多糖的关键因素，将在双聚糖缺陷小鼠和野生型小鼠之间进行糖尿病肾病的比较。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Nephropathy is a major complication of diabetes. Renal lipid and lipoprotein accumulation accelerates the progression of nephropathy. The mechanism leading to renal lipoprotein accumulation is unknown. Glomerulosclerosis, the characteristic lesion of diabetic nephropathy, is caused by increased deposition of mesangial matrix, including proteoglycans. There are numerous commonalities between the development of glomerulosclerosis and atherosclerosis. Proteoglycans have been shown to play a critical role in the initiation of atherosclerosis due to their ability to bind and retain lipoproteins. We have recently shown that renal proteoglycans demonstrate high lipoprotein binding affinity, and that TGF-b increases their LDL binding affinity. TGF-b is clearly shown to play a critical role in the development of diabetic nephropathy, and TGF-b levels are increased in diabetes. TGF-b stimulates the synthesis of extracellular matrix, including stimulation of the small proteoglycan biglycan. Thus, the increased TGF-b in diabetes may stimulate renal biglycan synthesis, which can mediate renal lipid accumulation and exacerbate progression of diabetic nephropathy. The overall goal of this grant is to test the hypothesis that renal lipid accumulation is mediated through interactions of lipoproteins with renal proteoglycans, especially biglycan. To determine if renal lipid accumulation is mediated via retention of LDL by proteoglycans, diabetic nephropathy will be compared between mice expressing proteoglycan-binding defective LDL and mice expressing wildtype LDL. To determine if biglycan is the key proteoglycan responsible, diabetic nephropathy will be compared between biglycan deficient and wildtype mice.