| Authors |
Keller MP, O'Connor C, Bitzer M, Schueler KL, Stapleton DS, Emfinger CH, Broman
AT, Hodgin JB, Attie AD
|
| Submitted By |
Submitted Externally on 4/25/2024 |
| Status |
Published |
| Journal |
Diabetes |
| Year |
2024 |
| Date Published |
2/1/2024 |
| Volume : Pages |
73 : 312 - 317 |
| PubMed Reference |
|
| Abstract |
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.
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