Role of angiotensin II in the expression and regulation of transforming growth factor-β in obstructive nephropathy

Abstract

Unilateral ureteral obstruction (UUO) leads to fibrosis of the obstructed kidney. We tested the hypothesis that interstitial fibrosis in UUO results, at least in part, from enhanced expression of transforming growth factor-β (TGF-β) which in turn is regulated by local angiotensin II (Ang II) generation. (The generic name TGF-β is used to discuss properties shared by all isoforms, but special reference to other isoforms is made when specifically needed.) Using Northern blot and immunohistochemical analysis, we examined the expression of TGF-β in rat kidneys after 24 hours (aUUO) and one week (cUUO) of obstruction. Obstructed kidneys from both periods had increased interstitial and perivascular TGF-β immunoreactivity compared to contralateral and sham kidneys, in which immunostaining was confined to the inner medulla. Relative abundance of all TGF-β mRNA isoforms were higher in the obstructed than in contralateral and sham kidneys in both aUUO and cUUO. Expression of TGF-β isoforms varied according to site (cortex vs. medulla), segment of the nephron, type of cells and duration of the obstruction. The increase in TGF-β immunoreactivity and mRNA levels in aUUO and cUUO was almost totally abolished by pretreatment with losartan. We conclude that in UUO: (a) TGF-β gene expression is increased and differentially regulated; (b) Ang II, at least partially, mediates the overexpression of TGF-β gene; and (c) Ang II may play a central role in fibrogenesis in this and other models of tubulointerstitial disease.