Transforming growth factor β1 and renal injury following subtotal nephrectomy in the rat: Role of the renin-angiotensin system

Transforming growth factor-β (TGF-β) and the renin-angiotensin system (RAS) have both been implicated in the pathogenesis of chronic renal disease. The present experiment investigated the chronology of TGF-β1 gene expression following subtotal nephrectomy (STNx) in the rat and the effect of blocking the RAS by angiotensin converting enzyme (ACE) inhibition or by angiotensin II receptor (AT₁) antagonism. Rats that had undergone subtotal nephrectomy developed hypertension, proteinuria, renal impairment, glomerulosclerosis, tubulointerstitial fibrosis and mononuclear cell infiltration. These changes were associated with a 2.5-fold increase in TGF-β1 gene expression during a 16-week time course. In situ hybridization localized TGF-β1 mRNA to sclerotic glomeruli, areas of tubulointerstitial injury and sites of mononuclear cell infiltration. Administration of the ACE inhibitor ramipril and the AT₁ receptor blocker valsartan blunted the increase in TGF-β1 mRNA, and attenuated the structural and functional manifestations of injury. These data suggest an interaction between the intrarenal RAS and TGF-β in the pathogenesis of the glomerular and tubulointerstitial fibrosis that follow a major reduction in renal mass.