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 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 weeks for systemic insulin resistance, albuminuria and glomerular histopathological and ultra-structural changes. Body weight and non-fasted blood glucose were increased by 8-weeks in both genders, while systemic insulin resistance commenced by 6-weeks in female and 8-weeks 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 weeks in the db/db DBA/2J cohort. Glomerulosclerosis, foot process effacement and glomerular basement membrane thickening were observed at 12-weeks of age in db/db DBA/2J mice. Compared to 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.
Østergaard, M. V., Ribeiro Pinto, V., Stevenson, K., Worm, J., Fink, L. N., & Coward, R. (2017). DBA2J db/db mice are susceptible to early albuminuria and glomerulosclerosis that correlates with systemic insulin resistance. AJP - Renal Physiology, 312(2), F312-F321. https://doi.org/10.1152/ajprenal.00451.2016