Transcriptional Profiling in Diabetic Nephropathy.

Case Western Reserve University, Cleveland OH

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Abstract

DESCRIPTION (provided by applicant): Renal injury triggers complicated molecular, cellular, and physiological responses difficult to study using conventional technology. Transcription profiling - a genome-scale determination of gene expression - is a promising new technology that might allow us to obtain quantitative information about the complex transcription profiles (i.e., transcriptome) that underlie renal failure. We will use high-density microarrays to map glomerular gene expression in a murine model of diabetic nephropathy. Specif[unreadable]c Aim 1 will map expression of>l 1,000 genes in freshly isolated glomeruli from db/db mice. We chose the db/db mouse model because it develops progressive renal insufficiency with features of type II diabetic nephropathy in humans. The gene expression profile will be constructed at an early stage when mice are hyperglycemic, but with little evidence of renal injury, and at a later stage characterized by overt diabetic nephropathy. In addition to identifying known and unknown genes differentially regulated in diabetic renal injury, we will used unsupervised and supervised learning tools to gain biological insight into the gene expression profiles. Specific Aim 2 will identify candidate genes linked to diabetic nephropathy by treating db/db mice with an angiotensin (ANG 11)-converting enzyme inhibitor, an anti-transforming growth factor Beta (TGFBeta) antibody, and both therapies combined. Aim 2 will thus identify transcription profiles altered by blocking ANG II and TGFBeta. These experiments will also discover genes altered in diabetes that are not affected by therapy and thus possibly linked to diabetic glomeruloscierosis. This pilot project will test the feasibility of transcription profiling to identify novel target genes for future mechanistic investigations into glomerular remodeling in diabetic nephropathy.