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J Am Soc Nephrol 11:616-624, 2000
© 2000 American Society of Nephrology

Locally Activated Renin-Angiotensin System Associated with TGF-ß1 as a Major Factor for Renal Injury Induced by Chronic Inhibition of Nitric Oxide Synthase in Rats

MINORU KASHIWAGI, MICHIYA SHINOZAKI, HIDEKI HIRAKATA, KIYOSHI TAMAKI, TADASHI HIRANO, MASANORI TOKUMOTO, HIROSHIGE GOTO, SEIYA OKUDA and MASATOSHI FUJISHIMA

Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Faculty of Medicine, Fukuoka, Japan.

Correspondence to Dr. Minoru Kashiwagi, Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka, 812-8582, Japan. Phone: +81 92 642 5256; Fax: +81 92 642 5271; E-mail: kashi{at}intmed2.med.kyushu-u.ac.jp

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-ß1 (TGF-ß1) 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-ß1 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-ß1 were equally emeliorated 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-ß1 expression is a major pathogenetic feature of renal injury in chronically NOS-inhibited rats.




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