The Genetic Architecture of Diabetic Nephropathy in Mice
- Diabetic Kidney Disease: Basic - II
November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
- Hodgin, Jeffrey B., University of Michigan, Ann Arbor, Michigan, United States
- Keller, Mark P., University of Wisconsin-Madison, Madison, Wisconsin, United States
- Bitzer, Markus, University of Michigan, Ann Arbor, Michigan, United States
- Attie, Alan, University of Wisconsin-Madison, Madison, Wisconsin, United States
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 (BTBRob/ob) develop hallmark glomerular features of diabetic kidney disease in humans, whereas leptin-deficient C57BL/6J (B6ob/ob) mice do not.
To identify the 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 used them to histologically score percent mesangial matrix and glomerular volume in ~50 glomeruli per mouse, yielding ~45,000 distinct measures in total. The same histological measurements were made in kidneys from B6 and BTBR mice when either lean or obese (Lepob/ob) 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.
We were able to identify a quantitative trait locus (QTL) on chromosome 7 at ~30 Mbp for percent mesangial matrix, glomerular volume, and mesangial volume. Two podocyte-specific genes in this region, Nphs1 (nephrin) and Kirrel2 (NEPH3 or filtrin), are physically located at the QTL and contain several high-impact SNPs (at splice regions or result in missense variants). Both are members of the immunoglobulin superfamily of cell adhesion molecules and localize to the podocyte slit diaphragm. Futhermore, mutations in these genes have been linked to chronic kidney disease in humans.
Our findings indicate genetic differences in genes known to be crucial to podocyte function and glomerular filtration barrier integrity as drivers of microstructural glomerular changes in diabetic nephropathy. Diabetic nephropathy is likely to be polygenic, with various genes, participating in various pathways, acting synergistically to affect susceptibility to the disease. Our study highlights Nphs1 and Kirrel2 and their role in podocyte function as genes that contributes to susceptibility to diabetic nephropathy and hallmark structural changes in the glomerulus. Genetic testing of a panel of gene variants may identify patients genetically predisposed to podocyte injury in diabetes and guide care to prevent nephropathy in diabetes.
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