Toward a mouse model of diabetic nephropathy: is endothelial nitric oxide synthase the missing link?

Why Is the Mouse Such a Poor Model for DN? Over the years, a number of mouse models of diabetes have been developed and studied. Although in-depth investigation of renal function and pathology has been somewhat limited, no mouse model to date exhibits the classic pathologic lesions of DN that are observed in humans: Glomerular nodulosclerosis, Kimmelstiel-Wilson nodules, fibrin drop lesions, or capsular drop lesions. Similarly, they also fail to develop characteristic functional features of overt DN in humans, including robust proteinuria and progressive loss of renal function. Many potential explanations have been proposed for the apparent resistance to the renal complications of diabetes in mice. One possibility is that the lifespan of a mouse is simply too short to permit complications that typically take a decade or more to develop in patients. Alternatively, there are a number of differences in dietary patterns and metabolism, including lipid and cholesterol pathways, that may affect susceptibility to nephropathy. Whereas hypertension is a common accompaniment and a major risk factor for progressive kidney injury in patients with diabetic nephropathy, normal or low BP is typical in hyperglycemic mice. Finally, the complex genetic and environmental overlay in patients with diabetes is much different from that in the current favorite strains of laboratory mice that are housed in “barrier” facilities devoid of pathogens. Within this array of potential factors, the articles from Zhao et al. (1) at Vanderbilt and Nakagawa et al. (2) at Florida suggest that endothelial function may be a key determinant for susceptibility to nephropathy in diabetic mice. Loss of Endothelial Nitric Oxide Synthase Produces Nodular Glomerular Disease in Diabetic Mice To examine the role of endothelial nitric oxide (eNO) in renal responses to diabetes, both groups induced diabetes in mice that carry a genetic deletion of the eNOS gene (2). Zhao et al. examined eNO synthase (eNOS) deficiency in the db/db mouse strain, a widely used model of type 2 diabetes. These mice carry a mutation in the leptin gene. On the typical C57BLKS/J background, renal disease in db/db mice is limited to the early features of DN with mild proteinuria, mesangial expansion, and mild thickening of the glomerular basement membrane (2). Nakagawa et al. carried out chemical induction of hyperglycemia using streptozotocin, which is toxic to islet cells. On wildtype backgrounds, streptozotocin-treated mice also typically develop only mild renal disease. The eNOS knockout mice lack the NOS-3 isoform that is responsible for a major portion of NO generation by endothelium. The most notable phenotype in nondiabetic eNOS mice is an increase in systolic BP and mild glomerular defects. Dysregulation of NO has been described in patients with DN, including increased NO expression in early DN, followed by a marked downregulation. Furthermore, polymorphisms in the eNOS gene that lead to decreased eNOS expression have been associated with advanced DN in patients (3–6). Strikingly, in both studies, diabetic mice with deletions of eNOS developed profound glomerular changes with increased proteinuria, marked thickening of the glomerular basement membrane, mesangial expansion, and prominent nodular sclerosis. The eNOS-deficient db/db mice also developed an impressive reduction in GFR. Furthermore, these dramatic changes were largely rescued in the streptozotocin mice by insulin therapy. Taken together, these findings suggest an important facilitating role for endothelial dysfunction in the pathogenesis of diabetic kidney disease. Moreover, this critical role of eNOS seems to transcend the cause of diabetes because similar acceleration of renal injury was seen in models of type 1 and type 2 diabetes. eNOS modulates a number of endothelial functions, including vascular tone, and contributes to vasodilation and hyperfiltration, features of early DN. The articles suggest that loss of these functions promotes the development of kidney patholPublished online ahead of print. Publication date available at www.jasn.org.