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Am J Physiol Renal Physiol. 2017 Feb 1;312(2):F312-F321. doi: 10.1152/ajprenal.00451.2016. Epub 2016 Nov 16.

DBA2J db/db mice are susceptible to early albuminuria and glomerulosclerosis that correlate with systemic insulin resistance.

Author information

1
Global Research, Novo Nordisk, Måløv, Denmark.
2
Bristol Renal, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; and.
3
Department of Biochemistry, Bristol Royal Infirmary, Bristol, United Kingdom.
4
Bristol Renal, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; and richard.coward@bristol.ac.uk.

Abstract

Diabetic nephropathy (DN) is the leading cause of kidney failure in the world. To understand important mechanisms underlying this condition, and to develop new therapies, good animal models are required. In mouse models of type 1 diabetes, the DBA/2J strain has been shown to be more susceptible to develop kidney disease than other common strains. We hypothesized this would also be the case in type 2 diabetes. We studied db/db and wild-type (wt) DBA/2J mice and compared these with the db/db BLKS/J mouse, which is currently the most widely used type 2 DN model. Mice were analyzed from age 6 to 12 wk for systemic insulin resistance, albuminuria, and glomerular histopathological and ultrastructural changes. Body weight and nonfasted blood glucose were increased by 8 wk in both genders, while systemic insulin resistance commenced by 6 wk in female and 8 wk in male db/db DBA/2J mice. The urinary albumin-to-creatinine ratio (ACR) was closely linked to systemic insulin resistance in both sexes and was increased ~50-fold by 12 wk of age in the db/db DBA/2J cohort. Glomerulosclerosis, foot process effacement, and glomerular basement membrane thickening were observed at 12 wk of age in db/db DBA/2J mice. Compared with db/db BLKS/J mice, db/db DBA/2J mice had significantly increased levels of urinary ACR, but similar glomerular histopathological and ultrastructural changes. The db/db DBA/2J mouse is a robust model of early-stage albuminuric DN, and its levels of albuminuria correlate closely with systemic insulin resistance. This mouse model will be helpful in defining early mechanisms of DN and ultimately the development of novel therapies.

KEYWORDS:

albuminuria; diabetic nephropathy; genetic background; insulin resistance; kidney injury

PMID:
27852608
PMCID:
PMC5336587
DOI:
10.1152/ajprenal.00451.2016
[Indexed for MEDLINE]
Free PMC Article

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