Gupta P, Franco-Saenz R, Mulrow P J
Department of Medicine, Medical College of Ohio, Toledo 43699-0008.
Endocrinology. 1993 Mar;132(3):1184-8. doi: 10.1210/endo.132.3.8440178.
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.
转化生长因子（TGF-βs）正逐渐成为多种甾体激素产生细胞中甾体生成可能的自分泌调节因子。我们实验室最近发现，TGF-β1是基础状态以及促肾上腺皮质激素（ACTH）和双丁酰环磷腺苷（Bu）2cAMP刺激的醛固酮生成的强效抑制剂。在本研究中，我们调查了TGF-β1对钾离子和血管紧张素II（A-II）刺激的醛固酮生成的影响，以及TGF-β1抑制醛固酮生物合成的机制。在有无TGF-β1存在的情况下，将培养的肾小球带细胞在无血清的PFMR-4培养基中孵育。为了研究TGF-β1对醛固酮生物合成早期途径的影响，我们在存在氰基酮衍生物WIN 19,578的情况下研究孕烯醇酮的生成，该衍生物可阻断孕烯醇酮向孕酮的转化。TGF-β1将孕烯醇酮的生成从133.9±30.1 ng/10(6)细胞·小时抑制至68.7±25.4 ng/10(6)细胞·小时，并且将ACTH刺激的孕烯醇酮生成从764.6±127.7 ng/10(6)细胞·小时抑制至141.0±2.2 ng/10(6)细胞·小时。相比之下，TGF-β1并未抑制25-羟胆固醇刺激的孕烯醇酮生成。为了研究醛固酮生成的后期途径，我们添加了甾体前体脱氧皮质酮和皮质酮。TGF-β1显著抑制脱氧皮质酮和皮质酮刺激的醛固酮生成超过50%。TGF-β1抑制AII和钾离子诱导的醛固酮合成。这些观察结果表明，TGF-β1通过干扰胆固醇跨线粒体膜的转运以及抑制醛固酮生物合成的后期途径，抑制AII和钾离子诱导的醛固酮合成以及醛固酮生物合成的早期途径。
