MECHANISMS OF RENAL LIPID RETENTION IN DIABETIC NEPHROPATHY

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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.