Indolent course of tubulointerstitial disease in a mouse model of subpressor, low-dose nitric oxide synthase inhibition.
Deficiency of nitric oxide (NO) represents a consistent manifestation of endothelial dysfunction (ECD), and the 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 contributes to nephrosclerosis in the absence of other profibrotic factors. To emulate more closely the indolent course of ECD, the study was expanded to an in vivo model with N(G)-monomethyl-L-arginine (L-NMMA; mimics effects of asymmetric dimethylarginine) administered to mice in the drinking water at subpressor doses of 0.3 and 0.8 mg/ml for 3-6 mo. This resulted in subtle but significant morphological 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: 1) increased activity of the interstitial fibroblasts; 2) occasional detachment of endothelial cells from the basement membrane; 3) splitting of the vascular basement membrane; 4) focal fibrosis; and 5) 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 subpressor 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.
Stoessel
Adelina
A
Department of Anatomy, Charité Universitätsmedizin Berlin, Berlin, Germany.
Paliege
Alexander
A
Theilig
Franziska
F
Addabbo
Francesco
F
Ratliff
Brian
B
Waschke
Jens
J
Patschan
Daniel
D
Goligorsky
Michael S
MS
Bachmann
Sebastian
S
D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000473:pathology* / Q000648:ultrastructure; D007668:Kidney / Q000473:pathology* / Q000648:ultrastructure; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology*; D007962:Leukocytes / Q000473:pathology; D051379:Mice; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors*; D010974:Platelet Aggregation; D019323:omega-N-Methylarginine / Q000008:administration & dosage / Q000633:toxicity*
D019323:omega-N-Methylarginine; D052250:Nitric Oxide Synthase Type III