Mechanisms of Renal Lipid Accumulation in Diabetic Nephropathy

糖尿病肾病肾脂质蓄积机制

• 批准号: 8195615
• 负责人: LISA R TANNOCK
• 金额: --
• 依托单位: VA MEDICAL CENTER - LEXINGTON, KY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195615
• 关键词: Affinity; Albuminuria; Animal Model; Antibodies; Binding; Biological Models; Cells; Characteristics; Clinical Research; Complication; Complications of Diabetes Mellitus; Data; Deposition; Development; Diabetes Mellitus; Diabetic Nephropathy; Enalapril; End stage renal failure; Goals; Grant; Healthcare; High Prevalence; Hyperlipidemia; In Vitro; Individual; Inflammatory; Kidney; Kidney Diseases; Lesion; Leucine; Link; Lipids; Lipoproteins; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Mediating; Mediator of activation protein; Modeling; Morbidity - disease rate; Mus; Proteoglycan; Reporting; Research; Role; Testing; Therapeutic Intervention; Tissues; Transforming Growth Factor beta; Translating; Up-Regulation; Veterans; biglycan; diabetic; glomerulosclerosis; in vivo; inhibitor/antagonist; interest; mortality; mouse model; nephrogenesis; neutralizing antibody; novel; prevent; public health relevance; receptor binding; research study; type I and type II diabetes

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.

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，导致相当高的发病率和死亡率。尽管目前有最好的治疗方法，但仍有大量蛋白尿患者进展为终末期肾病。尽管这一进展的机制尚不完全清楚，但肾脏脂质和脂蛋白的积累已被证明会加速肾病的发展。肾脏脂质积累引发炎症细胞大量涌入，随后发展为肾小球硬化症，这是糖尿病肾病的特征性病变。肾小球硬化的特征是包括蛋白聚糖在内的系膜基质沉积增加。特别令人感兴趣的是，糖尿病患者肾脏中富含亮氨酸的小蛋白多糖（SLRP）双糖链的含量增加。 TGF-2 在糖尿病中升高，已知是糖尿病肾病发生和进展的关键介质，也会增加系膜基质沉积，包括双糖链蛋白聚糖表达增加。此外，我们还发现 TGF-2 可以增加肾蛋白多糖的大小和 LDL 结合亲和力。因此，糖尿病患者中 TGF-2 升高诱导肾蛋白聚糖（双糖链蛋白聚糖）合成增加可能是介导脂蛋白肾积聚的原因。该资助的总体目标是检验肾脂质积累是通过脂蛋白与肾蛋白聚糖（尤其是双糖链蛋白聚糖）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 LDL 的小鼠与表达野生型 LDL 的同窝小鼠的糖尿病肾病来进行测试。为了确定双糖链蛋白聚糖是否是导致糖尿病肾病的关键蛋白聚糖，将对双糖链蛋白聚糖缺陷小鼠和野生型小鼠之间的糖尿病肾病进行比较。该资助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脂质积累是否对糖尿病肾病的发生和进展有显着贡献，以及关键的蛋白多糖是否是双聚糖。该资助还将确定双糖链蛋白聚糖是否可作为体内 TGF-2 的天然抑制剂。因此，该提案的意义在于，它不仅确定了高脂血症和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（包括肾病）的患病率非常高。这项研究将确定或排除蛋白多糖作为导致糖尿病肾病的肾脏脂质积累的原因。该资助将在动物模型系统中证明这一概念，并且结果可以轻松转化为临床研究。最终目标是确定治疗干预的新靶点，以降低糖尿病肾病的发病率和死亡率。