MKL1 mediates TGF-β-induced CTGF transcription to promote renal fibrosis
MKL1 mediates TGF-β-induced CTGF transcription to promote renal fibrosis
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DOI：
10.1002/jcp.29356
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发表时间：
2019-10-21
影响因子：
5.6
通讯作者：
Xu, Yong
中科院分区：
文献类型：
--
作者：
Mao, Lei;Liu, Li;Xu, Yong
异常的纤维化损害了肾脏的结构和功能内稳态。它还预测终末期肾病(ESRD)患者的诊断较差。肾小管上皮细胞(RTEC)可以转分化为肌成纤维细胞，产生细胞外基质蛋白，促进肾脏纤维化。结缔组织生长因子(CTGF)是肾纤维化过程中RTECs上调的一种细胞因子。本研究探讨巨核细胞白血病1(MKL1)对CTGF转录的调节作用。小鼠MKL1基因缺失或药物抑制可减轻单侧输尿管梗阻后的肾纤维化。值得注意的是，小鼠缺乏MKL1会下调肾脏CTGF的表达。同样，在RTES中，MKL1被敲除或抑制可钝化转化生长因子-β诱导的CTGF的表达。此外，还发现MKL1通过与Smad3相互作用激活CTGF转录，直接与CTGF启动子结合。此外，MKL1还介导了p300和WDR5之间的相互作用，从而调节CTGF的转录。CTGF基因敲除可抑制转化生长因子-β诱导的RTE促纤维化反应。MKL1活性受CTGF的相互调节。总之，我们认为，靶向MKL1-CTGF轴可能会产生针对异常肾纤维化的新的治疗方案。
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 myofibroblasts 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-beta 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-beta 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.