Transforming growth factor-beta 1 inhibits aldosterone biosynthesis in cultured bovine zona glomerulosa cells.
Transforming growth factors (TGF beta s) are emerging as possible autocrine regulators of steroidogenesis in a variety of steroid hormone-producing cells. Our laboratory has recently shown that TGF beta 1 is a potent inhibitor of basal and ACTH- and (Bu)2cAMP-stimulated aldosterone production. In this study, we investigated the effects of TGF beta 1 on potassium- and angiotensin-II (A-II)-stimulated aldosterone and the mechanisms by which TGF beta 1 inhibits aldosterone biosynthesis. Cultured zona glomerulosa cells were incubated in serum-free PFMR-4 medium in the presence and absence of TGF beta 1. To investigate the effects of TGF beta 1 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. TGF beta 1 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, TGF beta 1 did not inhibit 25-hydroxycholesterol-stimulated pregnenolone production. To study the late pathway of aldosterone production, we added the steroid precursors deoxycorticosterone and corticosterone. TGF beta 1 significantly inhibited deoxycorticosterone- and corticosterone-stimulated aldosterone production by over 50%. TGF beta 1 inhibited the AII- and potassium-induced synthesis of aldosterone. These observations show that TGF beta 1 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.
Gupta
P
P
Department of Medicine, Medical College of Ohio, Toledo 43699-0008.
Franco-Saenz
R
R
Mulrow
P J
PJ
D000450:Aldosterone / Q000096:biosynthesis*; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D002470:Cell Survival; D002478:Cells, Cultured; D003345:Corticosterone / Q000494:pharmacology; D003900:Desoxycorticosterone / Q000494:pharmacology; D007700:Kinetics; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D011284:Pregnenolone / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D015384:Zona Glomerulosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D000451:Mineralocorticoid Receptor Antagonists; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D003900:Desoxycorticosterone; D000450:Aldosterone; D011284:Pregnenolone; D011188:Potassium; D003345:Corticosterone