Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice.
The aim of the present study was to investigate the role of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) and its degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH) in angiotensin II (ANG II)-induced hypertension and target organ damage in mice. Mice transgenic for the human DDAH1 gene (TG) and wild-type (WT) mice (each, n = 28) were treated with 1.0 microg kg(-1) min(-1) ANG II, 3.0 microg kg(-1) min(-1) ANG II, or phosphate-buffered saline over 4 wk via osmotic minipumps. Blood pressure, as measured by tail cuff, was elevated to the same degree in TG and WT mice. Plasma levels of ADMA were lower in TG than WT mice and were not affected after 4 wk by either dose of ANG II in both TG and WT animals. Oxidative stress within the wall of the aorta, measured by fluorescence microscopy using the dye dihydroethidium, was significantly reduced in TG mice. ANG II-induced glomerulosclerosis was similar between WT and TG mice, whereas renal interstitial fibrosis was significantly reduced in TG compared with WT animals. Renal mRNA expression of protein arginine methyltransferase (PRMT)1 and DDAH2 increased during the infusion of ANG II, whereas PRMT3 and endogenous mouse DDAH1 expression remained unaltered. Chronic infusion of ANG II in mice has no effect on the plasma levels of ADMA after 4 wk. However, an overexpression of DDAH1 alleviates ANG II-induced renal interstitial fibrosis and vascular oxidative stress, suggesting a blood pressure-independent effect of ADMA on ANG II-induced target organ damage.
D000450:Aldosterone / Q000097:blood; D000804:Angiotensin II / Q000633:toxicity*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D001794:Blood Pressure / Q000502:physiology; D004247:DNA / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D017382:Reactive Oxygen Species; D020133:Reverse Transcriptase Polymerase Chain Reaction
D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C487735:dimethylarginine; D000804:Angiotensin II; D000450:Aldosterone; D004247:DNA; D001120:Arginine