TRANSFORMING GROWTH FACTOR-BETA-1 INHIBITS ALDOSTERONE BIOSYNTHESIS IN CULTURED BOVINE ZONA GLOMERULOSA CELLS

Transforming growth factors (TGFbetas) are emerging as possible autocrine regulators of steroidogenesis in a variety of steroid hormone-producing cells. Our laboratory has recently shown that TGFbeta1 is a potent inhibitor of basal and ACTH- and (Bu)2cAMP-stimulated aldosterone production. In this study, we investigated the effects of TGFbeta1 on potassium- and angiotensin-II (A-II)-stimulated aldosterone and the mechanisms by which TGFbeta1 inhibits aldosterone biosynthesis. Cultured zona glomerulosa cells were incubated in serum-free PFMR-4 medium in the presence and absence of TGFbeta1. To investigate the effects of TGFbeta1 on the early pathway of aldosterone biosynthesis, we studied the production of pregnenolone in the presence of the cyanoketone derivative WIN 19,578, which blocks the conversion of pregnenolone to progesterone. TGFbeta1 inhibited pregnenolone production from 133.9 +/- 30.1 to 68.7 +/- 25.4 ng/10(6) cells . h, and the ACTH-stimulated production of pregnenolone was inhibited from 764.6 +/- 127.7 to 141.0 +/- 2.2 ng/10(6) cells . h. In contrast, TGFbeta1 did not inhibit 25-hydroxycholesterol-stimulated pregnenolone production. To study the late pathway of aldosterone production, we added the steroid precursors deoxycorticosterone and corticosterone. TGFbeta1 significantly inhibited deoxycorticosterone- and corticosterone-stimulated aldosterone production by over 50%. TGFbeta1 inhibited the AII- and potassium-induced synthesis of aldosterone. These observations show that TGFbeta1 inhibits AII- and potassium-induced aldosterone synthesis and the early pathway of aldosterone biosynthesis by interfering with the transport of cholesterol across the mitochondrial membrane as well as inhibiting the late pathway of aldosterone biosynthesis.