Mechanisms of Renal Lipid Accumulation in Diabetic Nephropathy

描述（由申请人提供）： 肾病是1型和2型糖尿病的主要并发症，其导致相当大的发病率和死亡率。尽管目前有最好的治疗方法，但仍有相当数量的白蛋白尿患者进展为终末期肾病。虽然这种进展的机制尚未完全了解，但肾脏脂质和脂蛋白积聚已被证明会加速肾病的发展。肾脏脂质积聚触发炎性细胞的流入，随后发展为肾小球硬化，这是糖尿病肾病的特征性病变。肾小球硬化的特征是肾小球系膜基质沉积增加，包括蛋白多糖。特别令人感兴趣的是，富含亮氨酸的小蛋白聚糖（SLRP）双糖链在糖尿病中的肾脏含量增加。TGF-2在糖尿病中升高，并且已知是糖尿病肾病发展和进展的关键介质，也增加系膜基质沉积，包括双糖链蛋白聚糖表达增加。此外，我们已经证明TGF-2增加了肾蛋白聚糖的大小和LDL结合亲和力。因此，在糖尿病中由升高的TGF-2诱导的肾蛋白聚糖（双糖链）合成增加可能是介导脂蛋白在肾内蓄积的原因。这项资助的总体目标是检验肾脂质蓄积是通过脂蛋白与肾蛋白聚糖，特别是双糖链蛋白聚糖的相互作用介导的假设。这将通过比较表达蛋白聚糖结合缺陷型LDL的小鼠与表达野生型LDL的同窝小鼠中的糖尿病肾病进行检测。为了确定双糖蛋白聚糖是否是关键的蛋白聚糖，将在双糖蛋白聚糖缺陷型和野生型小鼠之间比较糖尿病肾病。本授权中概述的实验将提供直接的体内实验数据，以确定蛋白聚糖介导的肾脏脂质蓄积是否显著促进糖尿病肾病的发生和进展，以及关键的蛋白聚糖是否是双糖蛋白聚糖。这项资助还将确定双糖蛋白聚糖是否在体内作为TGF-2的天然抑制剂。因此，这一建议的意义在于，它不仅确定了高脂血症和糖尿病肾病的联系机制，而且还将确定新的靶点，以预防或干预糖尿病肾病的发展。

DESCRIPTION (provided by applicant): Nephropathy is a major complication of both type 1 and type 2 diabetes which causes considerable morbidity and mortality. Despite best current treatments, significant numbers of individuals with albuminuria progress to end stage renal disease. Although the mechanisms underlying this progression are not fully understood, renal lipid and lipoprotein accumulation has been shown to accelerate the development of nephropathy. Renal lipid accumulation triggers an influx of inflammatory cells with subsequent development of glomerulosclerosis, the characteristic lesion of diabetic nephropathy. Glomerulosclerosis is characterized by increased deposition of mesangial matrix, including proteoglycans. Of particular interest, the renal content of the small leucine-rich proteoglycan (SLRP) biglycan is increased in diabetes. TGF-2, which is elevated in diabetes, and is known to be a key mediator of diabetic nephropathy development and progression, also increases mesangial matrix deposition, including increased expression of biglycan. Furthermore, we have shown that TGF-2 increases the size and LDL binding affinity of renal proteoglycans. Thus, increased renal proteoglycan (biglycan) synthesis induced by elevated TGF-2 in diabetes may be responsible for mediating the renal accumulation of lipoproteins. 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. This will be tested by comparing diabetic nephropathy in mice expressing proteoglycan-binding defective LDL with littermates expressing wildtype LDL. To determine if biglycan is the key proteoglycan responsible, diabetic nephropathy will be compared between biglycan deficient and wildtype mice. The experiments outlined in this grant will provide direct in vivo experimental data identifying if proteoglycan mediated renal lipid accumulation contributes significantly to the development and progression of diabetic nephropathy, and if the key proteoglycan is biglycan. This grant will also identify if biglycan serves as a natural inhibitor of TGF-2 in vivo. Thus, the significance of this proposal is that it not only identifies a mechanism linking hyperlipidemia and diabetic nephropathy, but also will identify novel targets to prevent or intervene in the development of diabetic nephropathy.