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首页> 外文期刊>American Journal of Physiology >Antagonistic effects of bone morphogenetic protein-4 and -7 on renal mesangial cell proliferation induced by aldosterone through MAPK activation.
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Antagonistic effects of bone morphogenetic protein-4 and -7 on renal mesangial cell proliferation induced by aldosterone through MAPK activation.

机译：骨形态发生蛋白4和-7对醛固酮通过MAPK激活诱导的肾小球膜细胞增殖的拮抗作用。

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摘要

Aldosterone and angiotensin II (ANG II) contribute to the development and progression of renal damage. Here we investigated the effects of bone morphogenetic proteins (BMPs) on renal cell proliferation evoked by aldosterone and ANG II with mouse mesangial cells, which express mineralocorticoid receptors (MR), ANG II type 1 receptors, and BMP signaling molecules. Aldosterone and ANG II stimulated mesangial cell mitosis and activated ERK1/2 and SAPK/JNK signaling. These aldosterone effects were neutralized by the MR antagonist eplerenone and inhibition of transcription or translation, suggesting the involvement of genomic activation via MR. BMP-4 and BMP-7 stimulated Smad1, -5, -8 signaling more potently than BMP-2 and BMP-6, leading to suppression of mesangial cell mitosis and MR expression. MAPK inhibitors including U-0126 and SP-600125, but not SB-203580, suppressed aldosterone-induced cellular DNA synthesis, implying that ERK1/2 and SAPK/JNK pathways play crucial roles in mesangial cell proliferation. BMP-4 and BMP-7 inhibited phosphorylation of ERK1/2 and SAPK/JNK induced by aldosterone while activating p38 pathway, resulting in inhibition of aldosterone-induced cell mitosis. In contrast, aldosterone modulated the mesangial BMP system by decreasing expression of ALK-3, BMP-4, and BMP-7 while increasing inhibitory Smad6 expression. Thus novel functional cross talk between the mesangial BMP system and aldosterone signaling was uncovered, in which inhibition of MAPK signaling and MR expression by BMP-4 and BMP-7 may be involved in ameliorating renal damage due to mesangial proliferation caused by aldosterone.
机译：醛固酮和血管紧张素II（ANG II）有助于肾脏损害的发生和发展。在这里，我们研究了骨形态发生蛋白（BMP）对醛固酮和ANG II与表达肾上腺皮质激素受体（MR），ANG II 1型受体和BMP信号分子的小鼠肾小球系膜细胞诱发的肾细胞增殖的影响。醛固酮和ANG II刺激系膜细胞有丝分裂并激活ERK1 / 2和SAPK / JNK信号传导。这些醛固酮的作用被MR拮抗剂依普利农中和并抑制了转录或翻译，表明通过MR参与了基因组激活。 BMP-4和BMP-7比BMP-2和BMP-6更有效地刺激Smad1，-5，-8信号转导，从而抑制了系膜细胞的有丝分裂和MR表达。 MAPK抑制剂（包括U-0126和SP-600125，但不包括SB-203580）抑制醛固酮诱导的细胞DNA合成，这暗示ERK1 / 2和SAPK / JNK途径在系膜细胞增殖中起关键作用。 BMP-4和BMP-7抑制醛固酮诱导的ERK1 / 2和SAPK / JNK的磷酸化，同时激活p38途径，从而抑制了醛固酮诱导的细胞有丝分裂。相反，醛固酮通过降低ALK-3，BMP-4和BMP-7的表达，同时增加抑制性Smad6的表达来调节系膜BMP系统。因此，发现了系膜BMP系统和醛固酮信号转导之间的新型功能性串扰，其中BMP-4和BMP-7对MAPK信号转导和MR表达的抑制可能与减轻由醛固酮引起的肾小球膜增生引起的肾损害有关。

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