Genetic analysis of obesity-induced diabetic nephropathy in BTBR mice

<p dir="ltr">Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the United States and has a significant impact on human suffering. Leptin-deficient BTBR mice (BTBR^{<em>ob/ob</em>}) develop hallmark features of obesity-induced diabetic nephropathy, whereas leptin-deficient C57BL/6J (B6^{<em>ob/ob</em>}) mice do not. To identify genetic loci that underlie this strain difference, we constructed an F2 intercross between BTBR^{<em>ob/ob</em>} and B6^{<em>ob/ob</em>} mice. We isolated kidneys from 460 F2 mice and histologically scored them for percent mesangial matrix and glomerular volume (~50 glomeruli per mouse), yielding ~45,000 distinct measures in total. The same histological measurements were made in kidneys from B6 and BTBR mice, either lean or obese (<i>Lep</i>^{<em>ob/ob</em>}) at 4 and 10 weeks of age, allowing us to assess the contribution of strain, age, and obesity on glomerular pathology. All F2 mice were genotyped for ~5,000 single nucleotide polymorphisms (SNPs), ~2,000 of which were polymorphic between B6 and BTBR, enabling us to identify a quantitative trait locus (QTL) on chromosome 7, with a peak at ~30 Mbp, for percent mesangial matrix, glomerular volume, and mesangial volume. The podocyte-specific gene, Nephrin (<i>Nphs1</i>) is physically located at the QTL and contains high-impact SNPs in BTBR, including several missense variants within the extracellular Ig-like domains.</p><p><br></p><p><br></p><p dir="ltr"><b>Article Highlights</b></p><p dir="ltr">· Diabetes is the leading cause of end-stage renal disease.</p><p dir="ltr">· We previously discovered that the BTBR mouse strain carrying the <i>ob</i> mutation at the <i>Leptin </i>gene is an excellent model of human diabetic nephropathy and has been widely adopted by basic scientists and the pharmaceutical industry.</p><p dir="ltr">· Genetic factors play a role in the susceptibility to diabetic nephropathy.</p><p dir="ltr">· We carried out a linkage study in a sample of mice generated from an intercross between the BTBR and C57BL/6J strains, carrying the <i>ob</i> mutation.</p><p dir="ltr">· We identified a single locus and provided evidence that the leading candidate gene at this locus is <i>Nephrin.</i></p>