TRANSFORMING-GROWTH-FACTOR BETA-1 AND RENAL INJURY FOLLOWING SUBTOTALNEPHRECTOMY IN THE RAT - ROLE OF THE RENIN-ANGIOTENSIN SYSTEM

Transforming growth factor-beta (TGF-beta) and the renin-angiotensin s ystem (RAS) have both been implicated in the pathogenesis of chronic r enal disease. The present experiment investigated the chronology of TG F-beta 1 gene expression following subtotal nephrectomy (STNx) in the rat and the effect of blocking the RAS by angiotensin converting enzym e (ACE) inhibition or by angiotensin II receptor (AT(1)) antagonism. R ats that had undergone subtotal nephrectomy developed hypertension, pr oteinuria, renal impairment, glomerulosclerosis, tubulointerstitial fi brosis and mononuclear cell infiltration. These changes were associate d with a 2.5-fold increase in TGF-beta 1 gene expression during a 16-w eek time course. In situ hybridization localized TGF-beta 1 mRNA to sc lerotic glomeruli, areas of tubulointerstitial injury and sites of mon onuclear cell infiltration. Administration of the ACE inhibitor ramipr il and the AT(1) receptor blocker valsartan blunted the increase in TG F-beta 1 mRNA, and attenuated the structural and functional manifestat ions of injury. These data suggest an interaction between the intraren al RAS and TGF-beta in the pathogenesis of the glomerular and tubuloin terstitial fibrosis that follow a major reduction in renal mass.