Genetic susceptibility to diabetic kidney disease is linked to promoter variants of XOR

Qin Wang, Haiying Qi, Yiming Wu, Liping Yu, Rihab Bouchareb, Shuyu Li, Emelie Lassén, Gabriella Casalena, Krisztian Stadler, Kerstin Ebefors, Zhengzi Yi, Shaolin Shi, Fadi Salem, Ronald Gordon, Lu Lu, Robert W. Williams, Jeremy Duffield, Weijia Zhang, Yuval Itan, Erwin BöttingerIlse Daehn

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

The lifetime risk of kidney disease in people with diabetes is 10–30%, implicating genetic predisposition in the cause of diabetic kidney disease (DKD). Here we identify an expression quantitative trait loci (QTLs) in the cis-acting regulatory region of the xanthine dehydrogenase, or xanthine oxidoreductase (Xor), a binding site for C/EBPβ, to be associated with diabetes-induced podocyte loss in DKD in male mice. We examine 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 QTLs. We also uncover promoter XOR orthologue variants in humans associated with high risk of DKD. We introduced the risk variant into the 5′-regulatory region of XOR in DKD-resistant mice, which resulted in increased Xor activity associated with podocyte depletion, albuminuria, oxidative stress and damage restricted to the glomerular endothelium, which increase further with type 1 diabetes, high-fat diet and ageing. Therefore, differential regulation of Xor contributes to phenotypic consequences with diabetes and ageing.

Original languageEnglish
Pages (from-to)607-625
Number of pages19
JournalNature Metabolism
Volume5
Issue number4
DOIs
StatePublished - Apr 2023

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