Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou 510006, China.
Mol Cell Endocrinol. 2018 Jan 15;460:123-133. doi: 10.1016/j.mce.2017.07.014. Epub 2017 Jul 13.
Advanced glycation end products (AGEs), formed at an accelerated rate under diabetes, play a role in inflammation and fibrosis in mesangial areas in diabetic nephropathy (DN). However, the transcriptional modulator that mediates the cellular response to AGEs remains largely obscure. Our goal was to determine whether myocardin-related transcription factor (MRTF)-A, a key protein involved in the transcriptional regulation of smooth muscle cell phenotype, was responsible for the glomerular mesangial cells (GMCs) injury by AGEs, and, if so, how MRTF-A promoted mesangial dysfunction initiated by AGEs. In this study, MRTF-A was activated by AGEs in terms of protein expression and nuclear translocation in rat GMCs. MRTF-A overexpression synergistically enhanced the induction of FN and ICAM-1 by AGEs. In contract, depletion of MRTF-A abrogated the pathogenic program triggered by AGEs. Then, by interfering with MRTF-A, STAT1, STAT3 and STAT5 nuclear translocation were observed and we screened out STAT5, which was decreased obviously when MRTF-A depleted. Further investigation showed that MRTF-A interacted with STAT5 and promoted its nuclear accumulation and transcriptional activity. Therefore, our present findings suggested a role of MRTF-A in AGEs-induced GMCs injury, and further revealed that the underlying molecular mechanism was related to activating the nuclear factor STAT5.
糖基化终产物（AGEs）在糖尿病患者体内的生成速度加快，在糖尿病肾病（DN）的肾小球系膜区中发挥炎症和纤维化作用。然而，介导细胞对 AGEs 反应的转录调节剂在很大程度上仍不清楚。我们的目标是确定肌球蛋白相关转录因子（MRTF）-A 是否是参与平滑肌细胞表型转录调控的关键蛋白，负责 AGEs 引起的肾小球系膜细胞（GMC）损伤，如果是这样，MRTF-A 如何促进 AGEs 引发的系膜功能障碍。在这项研究中，AGEs 在大鼠 GMCs 中通过蛋白表达和核转位激活 MRTF-A。MRTF-A 的过表达协同增强了 AGEs 诱导的 FN 和 ICAM-1 的诱导。相反，MRTF-A 的耗竭消除了 AGEs 引发的致病程序。然后，通过干扰 MRTF-A，观察到 STAT1、STAT3 和 STAT5 的核转位，并且我们筛选出当 MRTF-A 耗尽时明显减少的 STAT5。进一步的研究表明，MRTF-A 与 STAT5 相互作用，促进其核积累和转录活性。因此，我们目前的研究结果表明，MRTF-A 在 AGEs 诱导的 GMC 损伤中起作用，并进一步揭示了潜在的分子机制与激活核因子 STAT5 有关。
