Cold Shock Proteins Mediate GN with Mesangioproliferation.
Cold Shock Proteins Mediate GN with Mesangioproliferation.
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DOI：
10.1681/asn.2015121367
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发表时间：
2016-05
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影响因子：
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通讯作者：
Cheng Zhu;E. Sauter;A. Schreiter;Claudia R C van Roeyen;T. Ostendorf;J. Floege;F. Gembardt;C. Hugo;B. Isermann;J. Lindquist;P. Mertens
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作者：
Cheng Zhu;E. Sauter;A. Schreiter;Claudia R C van Roeyen;T. Ostendorf;J. Floege;F. Gembardt;C. Hugo;B. Isermann;J. Lindquist;P. Mertens
DNA结合蛋白A（DbpA）是人类冷休克蛋白超家族的成员，在细胞增殖、分化和应激反应中具有已知的功能。DbpA介导肾小管上皮细胞中紧密连接相关的活动，但DbpA在系膜细胞中的功能尚不清楚。在这里，我们发现DbpA蛋白的表达仅限于血管平滑肌细胞在健康的人肾组织，但深刻的诱导DbpA蛋白的表达在肾小球系膜区室在系膜增生性肾炎。在体外，使用慢病毒构建体耗尽或过度表达DbpA分别导致系膜细胞增殖的抑制或促进。由于血小板衍生生长因子B（PDGF-B）信号传导在系膜细胞增殖中具有关键作用，我们检测了PDGF-B对DbpA的调节作用。人和大鼠系膜细胞的体外研究证实了PDGF-B对DbpA转录本数量和蛋白水平的刺激作用。另外的体内研究显示DbpA在实验性大鼠抗Thy1.1肾炎和小鼠系膜增生性肾炎模型中上调。为了干扰PDGF-B信号传导，我们向肾炎大鼠注射PDGF-B中和适体或MEK/ERK抑制剂U 0126。两种干预措施均显著降低DbpA蛋白表达。相反，连续输注PDGF-B在健康大鼠中诱导DbpA表达主要在系膜室中。综上所述，这些结果表明DbpA是PDGF-B信号转导的新靶点，也是系膜细胞增殖的关键介质。
DNA binding protein A (DbpA) is a member of the human cold shock domain-containing protein superfamily, with known functions in cell proliferation, differentiation, and stress responses. DbpA mediates tight junction-associated activities in tubular epithelial cells, but the function of DbpA in mesangial cells is unknown. Here, we found DbpA protein expression restricted to vascular smooth muscle cells in healthy human kidney tissue but profound induction of DbpA protein expression within the glomerular mesangial compartment in mesangioproliferative nephritis. In vitro, depletion or overexpression of DbpA using lentiviral constructs led to inhibition or promotion, respectively, of mesangial cell proliferation. Because platelet-derived growth factor B (PDGF-B) signaling has a pivotal role in mesangial cell proliferation, we examined the regulatory effect of PDGF-B on DbpA. In vitro studies of human and rat mesangial cells confirmed a stimulatory effect of PDGF-B on DbpA transcript numbers and protein levels. Additional in vivo investigations showed DbpA upregulation in experimental rat anti-Thy1.1 nephritis and murine mesangioproliferative nephritis models. To interfere with PDGF-B signaling, we injected nephritic rats with PDGF-B neutralizing aptamers or the MEK/ERK inhibitor U0126. Both interventions markedly decreased DbpA protein expression. Conversely, continuous PDGF-B infusion in healthy rats induced DbpA expression predominantly within the mesangial compartment. Taken together, these results indicate that DbpA is a novel target of PDGF-B signaling and a key mediator of mesangial cell proliferation.