title: Unmasking of proteinuria in the course of genetic dissection of nonproteinuric diabetic nephropathy.
abstract: We previously described the development of nonproteinuric diabetic nephropathy (NPDN) in the Cohen diabetic rat (CDs), a model that simulates Type 2 diabetes in humans. Using linkage analysis in an F2 cross, we currently set out to investigate the mechanisms underlying NPDN. We crossbred between CDs and SBN/y, a nondiabetic rat strain, generated F1 and F2 progenies, fed them diabetogenic diet that elicits diabetes and NPDN in CDs but not in SBN/y, and determined metabolic and renal phenotypes. Over 5 mo, ∼75% of F2 developed a diabetic phenotype. In parallel, a nephropathy developed in F2, with glomerular filtration rate (GFR) declining in ∼25% and, unexpectedly, significant proteinuria appearing in ∼75%. We scanned the F2 genome with microsatellite markers and used linkage analysis to identify quantitative trait loci (QTLs). We detected diabetes-related QTLs on RNO4 and 13. We also detected two QTLs for the decline in GFR on RNO4 and 13 and another QTL for proteinuria on RNO13. The metabolic and renal-related QTLs overlapped. These results suggest that the mechanisms underlying the nephropathy in F2 are related to genes that map to RNO4 and 13, as well as a common genetic background for the development of diabetes and the renal disease. Our findings further indicate that proteinuria is inhibited in parental diabetic CDs, thus accounting for the nonproteinuric phenotype, but "unmasked" in diabetic F2 whose genome has been modified. Identifying the nature of the factor inhibiting proteinuria in diabetic CDs but not in F2 may provide a clue to treatment and prevention of proteinuria in diabetes.
authors.affiliation: Laboratory for Molecular Medicine and Israeli Rat Genome Center, Ben-Gurion University Barzilai Medical Center Campus, Ashkelon, Israel;
authors.forename: Yoram
authors.initials: Y
authors.lastname: Yagil
authors.forename: Diana
authors.initials: D
authors.lastname: Roif
authors.forename: Marina
authors.initials: M
authors.lastname: Sapojnikov
authors.forename: David
authors.initials: D
authors.lastname: Ben-Dor
authors.forename: Ana
authors.initials: A
authors.lastname: Tobar
authors.forename: Eliezer
authors.initials: E
authors.lastname: Rosenmann
authors.forename: Chana
authors.initials: C
authors.lastname: Yagil
mesh_terms: D000818:Animals; D019540:Area Under Curve; D020090:Chromosome Segregation / Q000235:genetics; D003404:Creatinine / Q000378:metabolism; D003433:Crosses, Genetic; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000378:metabolism; D005260:Female; D008040:Genetic Linkage; D005951:Glucose Tolerance Test; D006801:Humans; D007668:Kidney / Q000473:pathology; D008297:Male; D010641:Phenotype; D011507:Proteinuria / Q000235:genetics* / Q000378:metabolism; D040641:Quantitative Trait Loci / Q000235:genetics; D051381:Rats; D014508:Urea / Q000097:blood
chemical_list: D014508:Urea; D003404:Creatinine
keywords: Type 2 diabetes; genes; linkage analysis; nephropathy; quantitative trait loci