CONTRIBUTION OF RENAL ANGIOTENSIN-II TYPE-I RECEPTOR TO GENE EXPRESSIONS IN HYPERTENSION-INDUCED RENAL INJURY

Recent evidence indicates that transforming growth factor-beta 1 (TGF- beta 1) plays an important role in renal fibrosis via stimulation of e xtracellular matrix synthesis. The present study was undertaken to inv estigate the role of angiotensin II type I receptor (AT1 receptor) in hypertension-induced renal injury. Twenty-two-week-old stroke-prone sp ontaneously hypertensive rats (SHRSP), which had established hypertens ion and moderate renal damage, were orally given TCV-116, a selective non-peptide AT1 receptor antagonist (0.1, 1 or 10 mg/kg/day), enalapri l (10 mg/kg/day) or vehicle once a day for 10 weeks. At the end point of the treatment, we examined renal function, the gene expressions of TGF-beta 1 and extracellular matrix components in the interstitium [co llagen types I (COI) and III (COIII), fibronectin (FN)] and the baseme nt membrane (COIV and laminin), and renal microscopic morphology in ra ts aged 32 weeks. In vehicle-treated 32 week-old SHRSP with renal dysf unction and nephrosclerosis, renal mRNA levels for TGF-beta 1, COI, CO III, FN, COIV were all several-fold higher than in WKY. Thus, renal TG F-beta 1 gene expression was enhanced in SHRSP, which may contribute t o the increased renal expressions of COI, COIII, FN, COIV in SHRSP. Tr eatment with TCV-116 (0.1 mg/kg/day) in SHRSP, in spite of no reductio n of blood pressure, decreased renal mRNA levels for TGF-beta 1, COI, COIII, FN, COIV, being accompanied by the significant decrease in urin ary protein and albumin excretion, blood urea nitrogen and plasma crea tinine. Treatment with TCV-116 (10 mg/kg/day) in SHRSP decreased mRNAs for TGF-beta 1, COI, COIII, FN and COIV to almost the same levels as WKY, being associated with normalization of urinary protein and albumi n excretion and the prevention of nephrosclerosis, as judged by micros copic histological observations. On the other hand, the effects of ena lapril (10 mg/kg/day) on the above mentioned mRNA levels, renal functi on and renal morphology were weaker than those of TCV-116 (10 mg/kg/da y) and were as much as TCV-116 (1 mg/kg/day). These results suggest th at independently of hypotensive action, AT1 receptor antagonist has a potent renal protective effect by inhibiting the gene expression of re nal TGF-beta 1 and extracellular matrix components.