Aldosterone promotes fibronectin production through a Smad2-dependent TGF-β1 pathway in mesangial cells
Aldosterone promotes fibronectin production through a Smad2-dependent TGF-β1 pathway in mesangial cells
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DOI：
10.1016/j.bbrc.2006.07.057
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发表时间：
2006-09-15
影响因子：
3.1
通讯作者：
Gu, Yong
中科院分区：
文献类型：
--
作者：
Lai, Lingyun;Chen, Jing;Gu, Yong
越来越多的证据表明，醛固酮除了调节钠和钾的稳态外，还可以引起细胞外基质（ECM）的积累。肾小球系膜细胞产生细胞外基质的增加被认为参与了肾小球硬化的发病机制。目前的研究检查是否醛固酮也产生于肾系膜细胞，和醛固酮对ECM积累在这些细胞的影响。RT-PCR法检测培养的肾小球系膜细胞中醛固酮合成酶（ALDOSTERONE SYSTEMS，ALDOSTERONE SYSTEMS，ALDOSTERONE 1132）、盐皮质激素受体（mineralocorticoid receptor，MR）和11 β-HSD 2 mRNA的表达。通过放射免疫法直接检测培养液中的醛固酮来证实肾系膜细胞产生醛固酮的能力。Real-time RT-PCR结果显示，Ang Ⅱ和钾离子均能显著增强系膜细胞CYP 11B 2 mRNA的表达（P < 0.001和P < 0.05）。培养的系膜细胞暴露于醛固酮显著增加纤维连接蛋白的产生，从12.4 +/- 1.9增加到74.6 +/- 16.8 ng/ml（P < 0.05）。醛固酮受体拮抗剂螺内酯可阻断醛固酮诱导的纤维连接蛋白的产生。醛固酮还使TGF-β 1报告荧光素酶活性从0.8 +/- 0.1增加到1.7 +/- 0.1（P < 0.05）。Inummoblot显示醛固酮治疗后TGF-β 1蛋白表达增加。通过敲低Smad 2阻断TGF-β 1信号通路可显著减弱醛固酮诱导的纤维连接蛋白的产生。目前的研究表明，肾小球系膜细胞是局部醛固酮作用的靶点，其通过TGF-β 1/Smad 2信号通路促进ECM蛋白纤连蛋白的产生。(c)2006年爱思唯尔公司All rights reserved.
Accumulating evidence demonstrates that aldosterone can cause extra-cellular matrix (ECM) accumulation, in addition to regulating sodium and potassium homeostasis. Increased extra-cellular matrix production by renal glomerular mesangial cells has been suggested to be involved in pathogenesis of glomerular sclerosis. The present studies examine whether aldosterone is also produced in renal mesangial cells, and the effect of aldosterone on ECM accumulation in these cells. In cultured renal mesangial cells, aldosterone synthase (CYP I 1132), mineralocorticoid receptor (MR), and 11 beta-HSD2 mRNA expressions were detected by RT-PCR. The ability of renal mesangial cells to produce aldosterone was confirmed by directly detecting aldosterone in culture medium via radiommumoassay. Real-time RT-PCR showed that the expression of CYP11B2 mRNA in mesangial cells was significantly enhanced by AngII (P < 0.001) and by potassium (P < 0.05). Exposure of the cultured mesangial cells to aldosterone significantly increased fibronectin production from 12.4 +/- 1.9 to 74.6 +/- 16.8 ng/ml (P < 0.05). The aldosterone induced fibronectin production was abolished by aldosterone receptor antagonist spironolactone. Aldosterone also increased the TGF-beta 1 reporter luciferase activity from 0.8 +/- 0.1 to 1.7 +/- 0.1 (P < 0.05). Inummoblot showed TGF-beta 1 protein expression was increased following aldosterone treatment. Blocking TGF-beta 1 signaling pathway by knocking down Smad2 significantly blunted the aldosterone induced fibronectin production. The present studies indicate that renal mesangial cell is a target of local aldosterone action, which promotes ECM protein fibronectin production via TGF-beta 1/Smad2 signaling pathway. (c) 2006 Elsevier Inc. All rights reserved.