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.
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.
Kashiwagi
Minoru
M
Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Faculty of Medicine, Fukuoka, Japan.
Shinozaki
Michiya
M
Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Faculty of Medicine, Fukuoka, Japan.
Hirakata
Hideki
H
Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Faculty of Medicine, Fukuoka, Japan.
Tamaki
Kiyoshi
K
Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Faculty of Medicine, Fukuoka, Japan.
Hirano
Tadashi
T
Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Faculty of Medicine, Fukuoka, Japan.
Tokumoto
Masanori
M
Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Faculty of Medicine, Fukuoka, Japan.
Goto
Hiroshige
H
Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Faculty of Medicine, Fukuoka, Japan.
Okuda
Seiya
S
Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Faculty of Medicine, Fukuoka, Japan.
Fujishima
Masatoshi
M
Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Faculty of Medicine, Fukuoka, Japan.
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*
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