title: Locally activated renin-angiotensin system associated with TGF-beta1 as a major factor for renal injury induced by chronic inhibition of nitric oxide synthase in rats.
abstract: Chronic inhibition of nitric oxide synthase (NOS) is known to cause renal parenchymal injury with systemic hypertension. To elucidate the pathogenetic mechanism in renal damage induced by NOS inhibition, N(omega)-nitro-L-arginine methyl ester (L-NAME) was given orally for 12 wk in Wistar rats, and the roles of tissue renin-angiotensin system and transforming growth factor-beta1 (TGF-beta1) were investigated. BP and urinary protein excretion increased significantly in L-NAME rats compared with control rats, and glomerulosclerosis and interstitial fibrosis developed. In L-NAME rats, the cortical tissue levels of angiotensin-converting enzyme activity and angiotensin II were significantly higher than those in control rats. The cortical mRNA expressions of both TGF-beta1 and fibronectin were significantly elevated in L-NAME rats. Immunohistochemically, increased expressions of both fibronectin and alpha-smooth muscle actin were also revealed in L-NAME rats. In L-NAME rats, these histologic injuries and the increased expression of TGF-beta1 were equally ameliorated by either angiotensin-converting enzyme inhibitor or angiotensin II type 1 receptor antagonist, but not by hydralazine. In conclusion, the locally activated renin-angiotensin system in connection with the increased TGF-beta1 expression is a major pathogenetic feature of renal injury in chronically NOS-inhibited rats.
authors.affiliation: Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Faculty of Medicine, Fukuoka, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Kashiwagi
authors.affiliation: Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Faculty of Medicine, Fukuoka, Japan.
authors.forename: Michiya
authors.initials: M
authors.lastname: Shinozaki
authors.affiliation: Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Faculty of Medicine, Fukuoka, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Hirakata
authors.affiliation: Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Faculty of Medicine, Fukuoka, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Tamaki
authors.affiliation: Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Faculty of Medicine, Fukuoka, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Hirano
authors.affiliation: Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Faculty of Medicine, Fukuoka, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Tokumoto
authors.affiliation: Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Faculty of Medicine, Fukuoka, Japan.
authors.forename: Hiroshige
authors.initials: H
authors.lastname: Goto
authors.affiliation: Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Faculty of Medicine, Fukuoka, Japan.
authors.forename: Seiya
authors.initials: S
authors.lastname: Okuda
authors.affiliation: Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Faculty of Medicine, Fukuoka, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Fujishima
mesh_terms: D000199:Actins / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D004791:Enzyme Inhibitors; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D048289:Imidazolidines; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D007672:Kidney Cortex / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009130:Muscle, Smooth / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011507:Proteinuria / Q000652:urine; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*
chemical_list: D000199:Actins; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D004791:Enzyme Inhibitors; D005353:Fibronectins; D007093:Imidazoles; D048289:Imidazolidines; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D016212:Transforming Growth Factor beta; C065166:imidapril; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester