Unmasking of proteinuria in the course of genetic dissection of nonproteinuric diabetic nephropathy Academic Article uri icon

abstract

  • We previously described the development of non-proteinuric diabetic nephropathy (NPDN) in the Cohen Diabetic rat (CDs), a model that simulates type 2 diabetes in humans. We currently applied the positional cloning strategy to investigate the mechanisms underlying NPDN. We crossbred between CDs and SBN/y, a non-diabetic healthy rat strain. We generated F1 and F2 progenies and fed them diabetogenic diet that elicits diabetes and NPDN in CDs but not in SBN/y. We determined metabolic and renal phenotypes. Over 5 months, 75% of F2 developed a gradually intensifying diabetic phenotype. In parallel, GFR declined in 25% of F2. Unexpectedly, 75% of F2 developed significant proteinuria. We scanned the F2 genome with microsatellite markers and used linkage analysis to identify QTLs. We detected diabetes-related QTLs on RNO4, confirming a previously identified QTL, and on RNO13, a novel QTL. We also detected two novel QTLs for the decline in GFR on RNO4 and RNO13, and another novel QTL for proteinuria on RNO13. The metabolic and renal-related QTLs overlapped. We conclude that the mechanisms underlying NPDN are related to genes that map to RNO4 and 13, suggesting a common genetic background for the development of diabetes and the renal disease. Our findings further suggest that proteinuria is inhibited in diabetic CDs, thus accounting for the non-proteinuric phenotype, but "unmasked" in diabetic F2, which genome has been modified. Identifying the nature of the factor inhibiting the expression of proteinuria in CDs may provide a clue to treatment and prevention of proteinuria in diabetes.

publication date

  • January 1, 2014