Endothelin-1 stimulates contraction of rat glomerular mesangial cells and potentiates beta-adrenergic-mediated cyclic adenosine monophosphate accumulation.
Endothelin-1 stimulates contraction of rat glomerular mesangial cells and potentiates beta-adrenergic-mediated cyclic adenosine monophosphate accumulation.
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DOI：
10.1172/jci114505
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发表时间：
1990-03
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影响因子：
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通讯作者：
M. Simonson;Michael J. Dunn
中科院分区：
文献类型：
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作者：
M. Simonson;Michael J. Dunn
新分离的肽，内皮素-1（ET-1），是一种有效的升压剂，降低肾小球滤过率和肾小球超滤系数。最近的证据表明，ET-1通过激活磷酸肌醇级联来动员肾小球系膜细胞内的Ca ~（2+）[（Ca ~（2+）]i）。本实验旨在研究ET-1是否刺激系膜细胞收缩并调节PGE 2和cAMP的合成，从而抑制血管收缩剂诱导的系膜收缩。ET-1（大于或等于1 nM）减少了在I型胶原三维凝胶上培养的大鼠系膜细胞的横截面积。ET-1也引起复杂的重排的F-肌动蛋白微丝一致的能动性反应。收缩反应ET-1只发生在激活磷脂酶C的浓度，收缩不受二氢吡啶敏感的钙通道的封锁。离子霉素升高[Ca 2 +]i，与ET-1达到的[Ca 2 +]i浓度相当，也降低了系膜细胞横截面积。ET-1（0.1 μ M）也诱发[3 H]花生四烯酸释放和PGE 2合成增加5倍，以及PGF 2 α合成增加和TXB 2的微小变化。ET-1只在3-异丁基-1-甲基黄嘌呤的存在下引起细胞内cAMP积累的轻微增加。ET-1也增加了cAMP的产生，以响应异丙肾上腺素。TPA和离子霉素，单独和组合，未能模仿ET-1的增强作用，然而，吲哚美辛阻断ET-1诱导的增强异丙肾上腺素刺激的cAMP，这是恢复通过添加外源性10 nM PGE 2。因此，目前的数据表明，ET-1刺激肾小球系膜细胞收缩，通过药物力学耦合和激活磷脂酶A2产生PGE 2，PGF 2 α，和TXB 2。ET-1还通过PGE 2依赖性机制放大β肾上腺素能刺激的cAMP积累。
The newly isolated peptide, endothelin-1 (ET-1), is a potent pressor agent that reduces GFR and the glomerular ultrafiltration coefficient. Recent evidence demonstrates that ET-1 mobilizes intracellular Ca2+ [( Ca2+]i) in glomerular mesangial cells by activating the phosphoinositide cascade. The present experiments were designed to examine whether ET-1 stimulates mesangial cell contraction and regulates the synthesis of PGE2 and cAMP, which dampen vasoconstrictor-induced mesangial contraction. ET-1 (greater than or equal to 1 nM) reduced the cross-sectional area of rat mesangial cells cultured on three-dimensional gels of collagen type I. ET-1 also caused complex rearrangements of F-actin microfilaments consistent with a motile response. Contraction in response to ET-1 occurred only at concentrations that activate phospholipase C, and contraction was unaffected by blockade of dihydropyridine-sensitive Ca2+ channels. Elevation of [Ca2+]i with ionomycin, to equivalent concentrations of [Ca2+]i achieved with ET-1, also reduced mesangial cell cross-sectional area. ET-1 (0.1 microM) also evoked [3H]arachidonate release and a fivefold increase in PGE2 synthesis as well as increased synthesis of PGF2 alpha and small changes of TXB2. ET-1 caused a minor increase in intracellular cAMP accumulation only in the presence of 3-isobutyl-1-methylxanthine. ET-1 also amplified cAMP production in response to isoproterenol. TPA and ionomycin, alone and in combination, failed to mimic the potentiating effect of ET-1; however, indomethacin blocked ET-1-induced potentiation of isoproterenol-stimulated cAMP, which was restored by addition of exogenous 10 nM PGE2. Thus the present data demonstrate that ET-1 stimulates mesangial cell contraction via pharmacomechanical coupling and activates phospholipase A2 to produce PGE2, PGF2 alpha, and TXB2. ET-1 also amplified beta adrenergic-stimulated cAMP accumulation by a PGE2-dependent mechanism.