Smooth-muscle calponin in mesangial cells: Regulation of expression and a role in suppressing glomerulonephritis
Smooth-muscle calponin in mesangial cells: Regulation of expression and a role in suppressing glomerulonephritis
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DOI：
10.1681/asn.v132322
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发表时间：
2002-02-01
影响因子：
13.6
通讯作者：
Takahashi, K
中科院分区：
文献类型：
--
作者：
Sugenoya, Y;Yoshimura, A;Takahashi, K
已知碱性或h1钙调蛋白基因是平滑肌分化特异性基因，其编码参与调节平滑肌缩短速度的肌动蛋白结合蛋白。结果发现，培养的系膜细胞表达碱性钙调蛋白，并定位于沿着肌动蛋白丝。在参与肾小球系膜细胞病理生理学的生长因子中，包括血小板衍生生长因子-BB（PDGF-BB）、肿瘤坏死因子-α（TNF-α）和转化生长因子-β 1（TGF-β 1），TNF-α在mRNA和蛋白水平上有效下调碱性钙调蛋白表达，而TGF-β 1上调钙调蛋白表达。PDGF-BB还降低其mRNA表达。碱性钙调蛋白mRNA的半衰期被确定为是相似的TNF-α处理和未处理的系膜细胞，而细胞转染试验，使用荧光素酶报告基因构建体含有功能性碱性钙调蛋白启动子显示，TNF-α和PDGF-BB降低转录活性。由于TNF-α和PDGF-BB的刺激与系膜细胞增殖相关，碱性钙调蛋白可能在抑制系膜细胞增殖中发挥作用。根据尿蛋白排泄量、肾小球细胞结构和肾小球中增殖细胞核抗原阳性细胞数量的增加来判断，在钙调蛋白敲除小鼠中使用抗肾小球基底膜抗体治疗会诱导比野生型小鼠更严重的肾炎。这些结果表明，碱性钙调蛋白的表达可能是肾小球肾炎的内在调节。阐明肾小球系膜细胞基础钙调蛋白表达调控的分子机制，有助于进一步了解肾小球损伤反应的分子基础和发病机制。
The basic or h1 calponin gene, which encodes an actin-binding protein involved in the regulation of smooth-muscle shortening velocity, is known to be a smooth-muscle differentiation-specific gene. It was found that basic calponin was expressed by cultured mesangial cells and localized along the actin filaments. Among the growth factors involved in the mesangial cell pathophysiology, including platelet-derived growth factor-BB (PDGF-BB), tumor necrosis factor-alpha (TNF- alpha), and transforming growth factor-beta1 (TGF-beta1), TNF-alpha potently downregulates basic calponin expression in both the mRNA and protein levels, whereas TGF-beta1 upregulates the calponin expression. PDGF-BB also reduced its mRNA expression. The half-life of basic calponin mRNA was determined to be similar between TNF-alpha-treated and -untreated mesangial cells, whereas cell transfection assays that used a luciferase reporter gene construct containing the functional basic calponin promoter showed that TNF-alpha and PDGF-BB reduced the transcriptional activity. Because stimulation with TNF-alpha and PDGF-BB was associated with mesangial cell proliferation, basic calponin may play a role in the suppression of mesangial cell proliferation. Treatment with anti-glomerular basement membrane antibody in calponin knockout mice induced more severe nephritis than in wild type mice, as judged from an increase in the urinary protein excretion, glomerular cellularity, and number of proliferating cell nuclear antigen-positive cells in glomerulus. These results suggest that basic calponin expression may serve as one of the intrinsic regulators of glomerular nephritis. Elucidation of the molecular mechanisms for regulation of the basic calponin expression in mesangial cells may improve the understanding of the molecular basis and pathogenesis of the glomerular response to injury.