Title

Genetic characterization of early renal changes in a novel mouse model of diabetic kidney disease

Document Type

Journal Article

Publication Title

Kidney International

Publisher

Elsevier

School

School of Medical and Health Sciences

RAS ID

29771

Funders

Diabetes Research Foundation of Western Australia

Australian Kidney foundation

National Health and Medical Research Council

Grant Number

NHMRC Number : 1037321

Comments

Originally published as: Balmer, L. A., Whiting, R., Rudnicka, C., Gallo, L. A., Jandeleit, K. A., Chow, Y., ... Morahan, G. (2019). Genetic characterization of early renal changes in a novel mouse model of diabetic kidney disease. Kidney International, 96(4), 918-926. Original publication available here

Abstract

Genetic factors influence susceptibility to diabetic kidney disease. Here we mapped genes mediating renal hypertrophic changes in response to diabetes. A survey of 15 mouse strains identified variation in diabetic kidney hypertrophy. Strains with greater (FVB/N(FVB)) and lesser (C57BL/6 (B6)) responses were crossed and diabetic F2 progeny were characterized. Kidney weights of diabetic F2 mice were broadly distributed. Quantitative trait locus analyses revealed diabetic mice with kidney weights in the upper quartile shared alleles on chromosomes (chr) 6 and 12; these loci were designated as Diabetic kidney hypertrophy (Dkh)-1 and -2. To confirm these loci, reciprocal congenic mice were generated with defined FVB chromosome segments on the B6 strain background (B6.Dkh1/2f) or vice versa (FVB.Dkh1/2b). Diabetic mice of the B6.Dkh1/2f congenic strain developed diabetic kidney hypertrophy, while the reciprocal FVB.Dkh1/2b congenic strain was protected. The chr6 locus contained the candidate gene; Ark1b3, coding aldose reductase; the FVB allele has a missense mutation in this gene. Microarray analysis identified differentially expressed genes between diabetic B6 and FVB mice. Thus, since the two loci identified by quantitative trait locus mapping are syntenic with regions identified for human diabetic kidney disease, the congenic strains we describe provide a valuable new resource to study diabetic kidney disease and test agents that may prevent it.

DOI

10.1016/j.kint.2019.04.031

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