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，可导致相当大的发病率和死亡率。尽管目前的治疗是最好的，但仍有相当数量的蛋白尿患者进展为终末期肾病。虽然这一进展的机制还不完全清楚，但肾脏脂质和脂蛋白积聚已被证明加速了肾病的发展。肾脏脂质堆积触发炎症细胞的涌入，继而发展为肾小球硬化，这是糖尿病肾病的特征病变。肾小球硬化的特征是系膜基质沉积增加，包括蛋白多糖。特别有趣的是，糖尿病患者肾脏中富含亮氨酸的蛋白多糖(SLRP)双聚糖的含量增加。转化生长因子-2在糖尿病中升高，被认为是糖尿病肾病发生和发展的关键介质，也增加了系膜基质的沉积，包括增加了Biglycan的表达。此外，我们还表明，转化生长因子-2增加了肾脏蛋白多糖的大小和与低密度脂蛋白的结合亲和力。因此，糖尿病时转化生长因子-2升高引起的肾脏蛋白多糖(双聚糖)合成增加可能是介导肾组织脂蛋白蓄积的原因之一。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。这将通过比较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的糖尿病肾病来进行测试。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。这项赠款中概述的实验将提供直接的体内实验数据，以确定蛋白多糖介导的肾脏脂质堆积是否对糖尿病肾病的发生和发展有重要贡献，以及关键的蛋白多糖是否为二聚糖。这笔赠款还将确定Biglycan是否在体内作为转化生长因子-2的天然抑制物。因此，这项建议的意义在于，它不仅确定了高脂血症与糖尿病肾病之间的联系机制，而且还将确定预防或干预糖尿病肾病发展的新靶点。 公共卫生相关性： 对退伍军人医疗保健的潜在影响：退伍军人糖尿病、高脂血症和糖尿病并发症的患病率非常高，包括肾病。这项研究将确定或排除蛋白多糖是导致糖尿病肾病的肾脏脂质堆积的原因。这笔拨款将在动物模型系统中证明这一概念，结果可以很容易地转化为临床研究。最终目标是为治疗干预寻找新的靶点，以降低糖尿病肾病的发病率和死亡率。

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. PUBLIC HEALTH RELEVANCE: Potential Impact on Veterans Health Care: Veterans have very high prevalence of diabetes, hyperlipidemia and diabetes complications, including nephropathy. This research will either identify or exclude proteoglycans as a cause of renal lipid accumulation contributing to diabetic nephropathy. The grant will prove the concept in an animal model system and the results can be easily translated into clinical research. The ultimate goal is to identify novel targets for therapeutic intervention, to decrease the morbidity and mortality of diabetic nephropathy.