Locally activated renin-angiotensin system associated with TGF-beta 1 as amajor 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 p arenchymal injury with systemic hypertension. To elucidate the pathogenetic mechanism in renal damage induced by NOS inhibition, N-omega-nitro-L-argin ine methyl ester (L-NAME) was given orally for 12 wk in Wistar rats, and th e roles of tissue renin-angiotensin system and transforming growth factor-b eta 1 (TGF-beta 1) were investigated. BP and urinary protein excretion incr eased significantly in L-NAME rats compared with control rats, and glomerul osclerosis and interstitial fibrosis developed. In L-NAME rats, the cortica l tissue levels of angiotensin-converting enzyme activity and angiotensin I I were significantly higher than those in control rats. The cortical mRNA e xpressions of both TGF-beta 1 and fibronectin were significantly elevated i n L-NAME rats. Immunohistochemically, increased expressions of both fibrone ctin 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-be ta 1 were equally ameliorated by either angiotensin-converting enzyme inhib itor 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-beta 1 expression is a major pathogenetic feature o f renal injury in chronically NOS-inhibited rats.