Hyperuricemic rats have a decrease in serum nitric oxide which is reversed by lowering uric acid levels. Soluble uric acid also impairs nitric oxide generation in cultured endothelial cells. Thus, hyperuricemia induces endothelial dysfunction; this may provide insight into a pathogenic mechanism by which uric acid may induce hypertension and vascular disease.

The pathogenesis of diabetic nephropathy remains far from clear, partly due to the lack of a suitable animal model that mimics human renal disease in type 2 diabetes. In this study, the natural history of renal manifestations in ZSF 1 rats, a recently developed rodent model of type 2 diabetes, is described. Male ZSF 1 rats developed obesity and hyperglycemia by 20 weeks of age on a highcarbohydrate diet. They also developed systolic and diastolic hypertension, hypercholesterolemia, profound hypertriglyceridemia, proteinuria, and renal failure. Renal histology demonstrated changes consistent with early diabetic nephropathy, including arteriolar thickening, tubular dilation and atrophy, glomerular basement membrane thickening, and mesangial expansion. Furthermore, renal nitric oxide production was decreased, and homogenates from renal cortices demonstrated reduced expression of renal endothelial and inducible nitric oxide synthases. These changes were associated with increased urinary levels and renal expression of 8-hydroxydeoxyguanosine, an indicator of mitochondrial oxidative stress, as well as with increased renal peroxynitrite formation. Administration of either insulin or the antioxidant alpha-lipoic acid decreased proteinuria and oxidative stress, but only the former slowed progression of renal failure. We conclude that ZSF 1 rats represent the best available rat model to study nephropathy from type 2 diabetes and that the renal lesions are associated with increased oxidative stress and decreased renal nitric oxide availability. 18: 294518: -295218: , 200718: . doi: 10.1681 Despite several recent advances, the pathogenesis of diabetic nephropathy (DN) remains far from clear. 1 The lack of suitable diabetic animal models that develop nephropathy akin to human disease is a major barrier for progress in this field. Notwithstanding the contribution to mechanistic pathways, the in vitro models to study DN have compounded the problem, necessitating more dependable in vivo animal models. Furthermore, the growing epidemic of metabolic syndrome warrants need for animal models that develop hyperlipidemia and obesity in addition to maturity-onset diabetes to mimic complications of human diabetes and metabolic syndrome. We report here a genetically engineered rat that developed features of DN as well as full-blown metabolic syndrome. Furthermore, decreased renal nitric oxide (NO) production was noted in these rats, consistent with our previous observations in mesangial cell cultures in vitro that were exposed to high ambient glucose concentrations. These changes were associated with increased oxidative stress, which partly accounted for decreased NO levels. J Am Soc Nephrol

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Nephropathy is a major microvascular complication of diabetes mellitus and often leads to terminal renal failure in addition to contributing significantly to cardiovascular morbidity and mortality. Despites continuous advances, the pathogenesis of diabetic nephropathy remains poorly understood. Recent studies have underscored the significance of structural and functional changes in podocytes in the development and progression of diabetic nephropathy. The role of podocytes in health and diabetic nephropathy and abnormalities including podocyte hypertrophy, effacement, and apoptosis, and a detailed discussion on the role played by the Wnt-β-catenin signaling pathway in podocyte injury and dysfunction are the focus of this review. In addition, the role played by Wnt signaling in mediating the effects of known therapeutic strategies for diabetic nephropathy is also discussed.