Mouse models of diabetic nephropathy

Abstract

Purpose of review: Progress in identification of effective therapies for diabetic nephropathy continues to be limited by the lack of ideal animal models. Here we review the current status of some leading murine models of this disorder.

Recent findings: A consensus statement of the Animals Models of Diabetic Complications Consortium sets forth guidelines and standards for measuring renal function and structural parameters necessary for validating murine models of diabetic nephropathy. Two murine models exploiting endothelial nitric oxide synthase (eNOS) deficiency as a major susceptibility factor for development of diabetic nephropathy are among the very few options for studying features of advanced diabetic nephropathy. Akita and OVE26 mice with mutations that result in Type I diabetes are also useful models of diabetic nephropathy. The recently described BTBR ob/ob (leptin deficient) mouse with Type II diabetes demonstrates key features of early podocyte loss and mesangiolysis characteristic of human diabetic nephropathy.

Summary: While there are many murine models of mesangial matrix expansion in the setting of diabetes, few progress to develop advanced diabetic lesions. Mice with eNOS deficiency, OVE26 mice, and the recently described BTBR ob/ob mouse currently appear to be the best murine models of advanced disease. A model that allows testing of interventions that modulate podocyte loss and regeneration, such as the BTBR ob/ob mouse, may be of particular benefit in developing therapeutics for diabetic nephropathy.

Figure 1

BTBR ob/ob mice show distinct mesangial expansion at 14 wks (B) compared to BTBR wild type (A). These mesangial lesions are progressive as shown at 21 wks (C, D) and result in part from mesangiolysis, with lucency and dissolution of the mesangial (C, arrow). The glomerulus in D shows diffuse and focally nodular mesangial sclerosis (arrowhead) and hyalinosis of an arteriole (D, arrow). Compare to human DN in E with characteristic hyalinosis of arteriole (arrow) and nodular sclerosis (arrowhead), and to the limited mesangial change in leptin receptor deficient db/db mice (F), currently the most widely used murine model of DN in Type II diabetes, at 22 weeks. A–F, silver methenamine stain. Modified from Hudkins KL et al. J Am Soc Nephrol. 2010; 21:1533–1542, reprinted with permission.