Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the U.S. and has a significant impact on human suffering. Leptin-deficient BTBR (BTBRob/ob) mice develop hallmark features of obesity-induced DN, whereas leptin-deficient C57BL/6J (B6ob/ob) mice do not. To identify genetic loci that underlie this strain difference, we constructed an F2 intercross between BTBRob/ob and B6ob/ob 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 (Lepob/ob), at 4 and 10 weeks of age, allowing us to assess the contribution of strain, age, and obesity to 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 (Nphs1) is physically located at the QTL and contains high-impact SNPs in BTBR, including several missense variants within the extracellular immunoglobulin-like domains.

Article Highlights
  • Diabetes is the leading cause of end-stage renal disease.

  • We previously discovered that the BTBR mouse strain carrying the ob mutation at the leptin gene is an excellent model of human diabetic nephropathy and has been widely adopted by basic scientists and the pharmaceutical industry.

  • Genetic factors play a role in susceptibility to diabetic nephropathy. We carried out a linkage study in a sample of mice generated from an intercross between the BTBR and C57BL/6J strains carrying the ob mutation.

  • We identified a single locus and provided evidence that the leading candidate gene at this locus is nephrin.

This article contains supplementary material online at https://doi.org/10.2337/figshare.24449989.

J.B.H. and A.D.A. are joint senior authors.

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