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MKL1 mediates TGF‐β‐induced CTGF transcription to promote renal fibrosis
Author(s) -
Mao Lei,
Liu Li,
Zhang Tianyi,
Wu Xiaoyan,
Zhang Tao,
Xu Yong
Publication year - 2020
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.29356
Subject(s) - ctgf , gene knockdown , cancer research , fibrosis , growth factor , transcription factor , transforming growth factor , extracellular matrix , transforming growth factor beta , biology , microbiology and biotechnology , medicine , apoptosis , gene , genetics , receptor
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‐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.