Endothelial nitric oxide synthase (eNOS) deficiency may contribute to the pathogenesis of diabetic nephropathy in both experimental models and humans, but the underlying mechanism is not fully understood. Here, we studied two common sequelae of endothelial dysfunction in diabetes: glomerular capillary growth and effects on neighboring podocytes. Streptozotocin-induced diabetes increased glomerular capillary volume in both C57BL/6 and eNOS 2/2 mice. Inhibiting the vascular endothelial growth factor receptor attenuated albuminuria in diabetic C57BL/6 mice but not in diabetic eNOS 2/2 mice, even though it inhibited glomerular capillary enlargement in both. In eNOS 2/2 mice, an acute podocytopathy and heavy albuminuria occurred as early as 2 weeks after inducing diabetes, but treatment with either captopril or losartan prevented these effects. In vitro, serum derived from diabetic eNOS 2/2 mice augmented actin filament rearrangement in cultured podocytes. Furthermore, conditioned medium derived from eNOS 2/2 glomerular endothelial cells exposed to both high glucose and angiotensin II activated podocyte RhoA. Taken together, these results suggest that the combined effects of eNOS deficiency and hyperglycemia contribute to podocyte injury, highlighting the importance of communication between endothelial cells and podocytes in diabetes. Identifying mediators of this communication may lead to the future development of therapies targeting endothelial dysfunction in albuminuric individuals with diabetes.

Background/Aims: While experimental models that emulate diabetic nephropathy are valuable tools for elucidating pathogenetic mechanisms and developing novel therapies, existing models imperfectly recapitulate human disease. In diabetes, hyperglycemia and hemodynamic forces act in concert to induce renal injury. Accordingly, in the present study, we combined streptozotocin-induced diabetes with surgical ablation of 5/6 of the kidney mass with the aim of evaluating their additive effects on renal function and glomerular morphology. Methods: Female F344 rats were randomized to undergo subtotal nephrectomy (SNx) either at baseline or following 4 weeks of diabetes. Results: In comparison to sham rats, rats with diabetes or rats after SNx surgery, diabetic subtotally nephrectomized (DM-SNx) rats demonstrated an increase in systolic blood pressure, glomerular volume and mesangial matrix. Albuminuria was synergistically increased by hyperglycemia and renal mass ablation associated with decreased nephrin expression. In contrast, glomerular capillary rarefaction and glomerular filtration rate were similarly reduced in SNx and DM-SNx rats. Conclusion: The DM-SNx rat recapitulates some of the features of human disease, most notably augmented albuminuria. Since this model avoids the deletion or overexpression of gene(s) linked to the pathogenesis of nephropathy, the DM-SNx rat model represents a complementary tool for the trial of novel therapies.