Distinguished Scientist Seminar Series featuring Ilse Daehn, PhD – “Genetic Susceptibility to Diabetic Kidney Disease is linked to a promoter variant of XOR.”

Distinguished Scientist Seminar Series

Ilse Daehn, PhD
Associate Professor
Dept. Medicine, Nephrology
The Icahn School of Medicine at Mount Sinai

Title & Abstract:

“Genetic Susceptibility to Diabetic Kidney Disease is linked to a promoter variant of XOR.”

The lifetime risk of kidney disease in patients with diabetes is 10%-30%, implicating genetic predisposition in the cause of diabetic kidney disease (DKD). Here we examined mouse inbred strains that are susceptible (DBA/2J) and resistant (C57BL/6J) to DKD, as well as a panel of recombinant inbred BXD mice, to map quantitative trait loci (QTLs) associated with diabetes-induced podocyte loss in DKD. An expression QTL was identified in the cis-acting regulatory region of the xanthine oxidoreductase (XOR), a binding site for C/EBPβ. We also uncovered promoter XOR orthologue variants in humans associated with high-risk for DKD. We next introduced the risk variant into the 5’-regulatory region of XOR in DKD resistant mice, resulting in increased XOR activity associated with podocyte depletion, albuminuria, oxidative stress and damage restricted to the glomerular endothelium with Type I diabetes, high fat diet and with aging. Therefore, differential regulation of XOR contributes to phenotypic consequences with diabetes and aging.