ROLE OF ANGIOTENSIN-II IN THE EXPRESSION AND REGULATION OF TRANSFORMING GROWTH-FACTOR-BETA IN OBSTRUCTIVE NEPHROPATHY

Unilateral ureteral obstruction (UUO) leads to fibrosis of the obstruc ted kidney. We tested the hypothesis that interstitial fibrosis in UUO results, at least in part, from enhanced expression of transforming g rowth factor-beta (TGF-beta) which in turn is regulated by local angio tensin II (Ang II) generation. (The generic name TGF-beta is used to d iscuss properties shared by all isoforms, but special reference to oth er isoforms is made when specifically needed.) Using Northern blot and immunohistochemical analysis, we examined the expression of TGF-beta in rat kidneys after 24 hours (aUUO) and one week (cUUO) of obstructio n. Obstructed kidneys from both periods had increased interstitial and perivascular TGF-beta immunoreactivity compared to contralateral and sham kidneys, in which immunostaining was confined to the inner medull a. Relative abundance of all TGF-beta mRNA isoforms were higher in the obstructed than in contralateral and sham kidneys in both aUUO and cU UO. Expression of TGF-beta isoforms varied according to site (cortex v s. medulla), segment of the nephron, type of cells and duration of the obstruction. The increase in TGF-beta immunoreactivity and mRNA level s in aUUO and cUUO was almost totally abolished by pretreatment with l osartan. We conclude that in UUO: (a) TGF-beta gene expression is incr eased and differentially regulated; (b) Ang II, at least partially, me diates the overexpression of TGF-beta gene; and (c) Ang II may play a central role in fibrogenesis in this and other models of tubulointerst itial disease.