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首页> 外文期刊>Journal of cellular physiology. >MKL1 mediates TGF-p-induced CTGF transcription to promote renal fibrosis
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MKL1 mediates TGF-p-induced CTGF transcription to promote renal fibrosis

机译：MKL1介导TGF-p-induced CTGF转录促进肾纤维化

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摘要

Aberrant fibrogenesis impairs the architectural and functional homeostasis of the kidneys. It also predicts poor diagnosis in patients with end-stage renal disease (ESRD). Renal tubular epithelial cells (RTEC) can trans-differentiate into myofibro-blasts to produce extracellular matrix proteins and contribute to renal fibrosis. Connective tissue growth factor (CTGF) is a cytokine upregulated in RTECs during renal fibrosis. In the present study, we investigated the regulation of CTGF transcription by megakaryocytic leukemia 1 (MKL1). Genetic deletion or pharmaceutical inhibition of MKL1 in mice mitigated renal fibrosis following the unilateral ureteral obstruction procedure. Notably, MKL1 deficiency in mice downregulated CTGF expression in the kidneys. Likewise, MKL1 knockdown or inhibition in RTEs blunted TGF-β induced CTGF expression. Further, it was discovered that MKL1 bound directly to the CTGF promoter by interacting with SMAD3 to activate CTGF transcription. In addition, MKL1 mediated the interplay between p300 and WDR5 to regulate CTGF transcription. CTGF knockdown dampened TGF-β induced pro-fibrogenic response in RTEs. MKL1 activity was reciprocally regulated by CTGF. In conclusion, we propose that targeting the MKL1-CTGF axis may generate novel therapeutic solutions against aberrant renal fibrogenesis.
机译：异常纤维发生损害的架构和功能肾脏的体内平衡。还预测贫困患者的诊断终末期肾病(ESRD)。上皮细胞(RTEC)可以trans-differentiate到myofibro-blasts产生细胞外矩阵蛋白,导致肾脏纤维化。结缔组织生长因子(CTGF)细胞因子调节RTECs在肾纤维化CTGF转录的调控巨核细胞的白血病1 (MKL1)。删除或制药MKL1抑制老鼠后减轻肾纤维化单侧输尿管梗阻的过程。值得注意的是,MKL1缺乏小鼠表达下调CTGF表达在肾脏。击倒或抑制rt钝化TGF -β诱导CTGF的表达。发现MKL1直接绑定到CTGF通过与SMAD3交互激活启动子CTGF转录。p300和WDR5规范之间的相互作用CTGF转录。rt诱导pro-fibrogenic反应。活动被CTGF相互地监管。结论,我们建议针对MKL1-CTGF轴可能产生新的治疗对异常的肾纤维发生的解决方案。

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