COL4A3 Variants and Susceptibility to Diabetic Nephropathy
Diabetic nephropathy (DN) is a major diabetic complication that affects a large fraction of both type I and II diabetic patients. One hallmark of DN is the dramatic thickening of the glomerular basement membrane (GBM). The GBM is an ~300 nm-thick layer of extracellular matrix composed of many different proteins, including collagen IV, laminin, nidogen, and heparan sulfate proteoglycan. It has been assumed for decades that the GBM thickening observed in diabetic nephropathy is directly related to the microalbuminuria and progression to frank proteinuria that occurs in the fraction of type I and type II diabetic patients who develop DN. Recently, Jose C. Florez of Harvard Medical School and colleagues posted the results of a high-powered genome-wide association study (GWAS) of diabetic kidney disease in type I patients. A non-synonymous variant in COL4A3 (p.Asp326Tyr) was found to protect against the development of DN. Here we propose to test the hypothesis that this COL4A3 variant results in a thinner than normal GBM in healthy mice and will reduce the extent of GBM thickening and diabetic nephropathy in type I diabetic mice. CRISPR/Cas9-mediated genome editing will be used to introduce the human alleles into the mouse Col4a3 gene in DBA/2J mice that have been shown to be susceptible to DN. Electron microscopy will be used to quantify GBM width, and urine and blood will be analyzed to determine whether the variant is protective. The results of these studies will indicate whether or not the variant has a direct impact on GBM width and severity of DN and whether modulation of GBM width should be viewed as a viable target for therapy in patients. Diabetic nephropathy is a major cause of kidney failure in the US, but there are no specific treatments to prevent it or stop its progression. Here we will test whether a change to a protein that helps form the kidney’s filtration barrier can protect from diabetic nephropathy in mice. The results of these studies could lead to new treatment strategies for human patients.

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