Mechanisms of Renal Lipid Accumulation in Diabetic Nephropathy

糖尿病肾病肾脂质蓄积机制

基本信息

批准号：
8391566
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
项目类别：
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/8391566
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

项目摘要

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.

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，会导致相当大的发病率和死亡率。尽管当前治疗最佳，但大量患有蛋白尿的人会发展为终结肾脏疾病。尽管该进展的基础机制尚未完全了解，但肾脏脂质和脂蛋白的积累已被证明可以加速肾病的发育。肾脏脂质积累会触发炎症细胞的涌入，随后发展，肾小球硬化是糖尿病肾病的特征性病变。肾小球硬化的特征是肾小球基质的沉积增加，包括蛋白聚糖。特别有趣的是，糖尿病中富含亮氨酸的小蛋白聚糖（SLRP）Biglycan的肾脏含量增加。 TGF-2在糖尿病中升高，已知是糖尿病性肾病发育和进展的关键介体，还增加了膜型基质沉积，包括增加Biglycan的表达。此外，我们已经表明TGF-2增加了肾脏蛋白聚糖的大小和LDL结合亲和力。因此，糖尿病中TGF-2诱导的肾脏蛋白聚糖（Biglycan）合成增加可能是负责介导脂蛋白的肾脏积累。这项赠款的总体目标是检验以下假设：肾脏脂质积累是通过脂蛋白与肾脏蛋白聚糖（尤其是大型糖果蛋白酶）相互作用来介导的。这将通过比较表达蛋白聚糖结合有缺陷的LDL的小鼠与表达野生型LDL的同窝鼠的小鼠中的糖尿病性肾病进行测试。为了确定Biglycan是否是关键的蛋白聚糖负责，将比较大型群体缺陷和野生型小鼠之间的糖尿病性肾病。该赠款中概述的实验将提供直接的体内实验数据，以识别蛋白聚糖介导的肾脏脂质积累是否有助于糖尿病性肾病的发展和进展，以及关键的蛋白聚糖是否是Biglycan。该赠款还将确定Biglycan是否是体内TGF-2的天然抑制剂。因此，该提议的意义在于，它不仅确定了连接高脂血症和糖尿病性肾病的机制，而且还将确定预防或干预糖尿病性肾病的新靶标。