Role of angiotensin II, endothelin-1, and nitric oxide in HgCl2-induced acute renal failure.
To elucidate the mechanisms underlying the development of HgCl2-induced acute renal failure (ARF), we examined the expression of endothelin (ET)-1, endothelial (e) nitric oxide synthase (NOS) and inducible (i) NOS, and a role of angiotensin II (ANG II) and tumor necrosis factor (TNF) in glomeruli and cortices from rats at 20 h after exposure of HgCl2. Prepro-ET-1 and iNOS mRNA were significantly increased in glomeruli and cortices from rats with HgCl2-induced ARF. However, eNOS mRNA was markedly decreased in glomeruli of rats with HgCl2-induced ARF. Blockade of the action of endogenous ANG II with TCV-116, an ANG II receptor type 1 antagonist, or prior administration of TNF antibody (Ab) neutralizing TNF bioactivity or aminoguanidine, an iNOS inhibitor, substantially suppressed the increase in the expression of prepro-ET-1 or iNOS mRNA seen in rats with HgCl2-induced ARF. Both TCV-116 and TNF Ab had no effects on the expression of eNOS mRNA. The abundance of ET-1, iNOS, and eNOS proteins was paralleled by the magnitude of each mRNA expression. Additionally, the aggravation of blood urea nitrogen and serum Cr observed in rats with HgCl2-induced ARF were significantly ameliorated together with the alleviation of proximal tubule epithelial cell injury when the expression of prepro-ET-1 or iNOS mRNA was blunted by prior administration of TCV-116 or prior injection of TNF Ab or aminoguanidine. These observations indicate that ANG II, ET-1, and NO may play an important role in the progression of HgCl2-induced ARF through the acceleration of proximal tubule epithelial cell injury and the deterioration of glomerular hemodynamics. In HgCl2-induced ARF, the gene expression of ET-1 or iNOS is at least in part up-regulated at the transcription level by endogenous ANG II or TNF.
Yanagisawa
H
H
Department of Hygiene and Preventive Medicine, Faculty of Medicine, Saitama Medical School, Japan.
Nodera
M
M
Umemori
Y
Y
Shimoguchi
Y
Y
Wada
O
O
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D000804:Angiotensin II / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001806:Blood Urea Nitrogen; D002857:Chromium / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D018450:Disease Progression; D019332:Endothelin-1 / Q000378:metabolism / Q000502:physiology*; D005260:Female; D007150:Immunohistochemistry; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D008627:Mercuric Chloride / Q000633:toxicity*; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D019332:Endothelin-1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D002857:Chromium; D000804:Angiotensin II; D009569:Nitric Oxide; D008627:Mercuric Chloride; D003404:Creatinine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D007703:Peptidyl-Dipeptidase A