TISSUE-SPECIFIC REGULATION OF GROWTH-FACTORS AND CLUSTERIN BY ANGIOTENSIN-II

Angiotensin II (ANG II) has been implicated in the hypertrophic and fi brotic responses of the heart and kidney to systemic hypertension. To determine whether these actions of ANG II are related to tissue-specif ic stimulation of growth factors, we infused adult Sprague-Dawley rats with ANG II at 50 ng/min (low dose), 100 ng/min (high dose), or vehic le for 1 week. Rats receiving vehicle or low-dose ANG II were normoten sive with normal plasma aldosterone concentration, whereas rats receiv ing high-dose ANG II were hypertensive with increased plasma aldostero ne. Tissue fibrosis was quantified morphometrically, and messenger RNA (mRNA) for transforming growth factor-beta(1) (TGF-beta(1)) and prepr o-epidermal growth factor (EGF) was measured in liver, heart, and rena l glomeruli and tubules. In addition, mRNA was determined for clusteri n, a glycoprotein expressed in response to tissue injury. Compared to vehicle, low-dose ANG II increased TGF-beta(1) expression in glomeruli , tubules, and heart, but not in liver, and increased EGF expression i n renal tubules only. High-dose ANG II decreased clusterin expression in liver only. Fibrosis was induced by low- and high-dose ANG II in ki dney and heart, but not in liver. We conclude that ANG II selectively stimulates TGF-beta(1) mRNA in the heart and kidney, which may contrib ute to cardiac and renal interstitial fibrosis resulting from activati on of the renin-angiotensin system independent of hypertension. By sti mulating cellular proliferation, selective stimulation by ANG II of EG F in renal tubules may amplify the effects of TGF-beta(1). Suppression of clusterin expression in the liver of hypertensive rats may represe nt a specific response to high levels of circulating ANG II or a respo nse to hypertensive injury. (C) 1998 American Journal of Hypertension, Ltd.