Deficiency of nitric oxide (NO) represents a consistent manifestation of endothelial dysfunction (ECD), and accumulation of asymmetric dimethylarginine occurs early in renal disease. Here, we confirmed in vitro and in vivo the previous finding that a fragment of collagen XVIII, endostatin, was upregulated by chronic inhibition of NO production and sought to support a hypothesis that primary ECD contribute to nephrosclerosis in absence of other profibrotic factors. To emulate closer the indolent course of ECD, the study was expanded to an in vivo model with L-NMMA (mimics effects of ADMA) administered to mice in the drinking water at sub-pressor doses of 0.3 and 0.8 mg/ml for 3-6 months. This resulted in subtle but significant morphologic alterations detected in kidneys of mice chronically treated with L-NMMA: 1) consistent perivascular expansion of interstitial matrix components at the inner stripe of the outer medulla and 2) collagen XVIII/endostatin abundance. Ultrastructural abnormalities were detected in L-NMMA-treated mice: a) increased activity of the interstitial fibroblasts; b) occasional detachment of endothelial cells from the basement membrane; c) splitting of the vascular basement membrane; d) focal fibrosis; and e) accumulation of lipofuscin by interstitial fibroblasts. Preembedding labeling of microvasculature with anti-CD31 antibodies showed infiltrating leukocytes and agglomerating platelets attaching to the visibly intact or denuded capillaries. Collectively, the data indicate that the mouse model of sub-pressor chronic administration of L-NMMA is not a robust one (endothelial pathology visible only ultrastructurally), and yet it closely resembles the natural progression of endothelial dysfunction, microvascular abnormalities and associated tubulointerstitial scarring.