An MRTF-A-ZEB1-IRF9 axis contributes to fibroblast-myofibroblast transition and renal fibrosis

Myofibroblasts, characterized by the expression of the matricellular protein periostin (Postn), mediate the profibrogenic response during tissue repair and remodeling. Previous studies have demonstrated that systemic deficiency in myocardin-related transcription factor A (MRTF-A) attenuates renal fibrosis in mice. In the present study, we investigated the myofibroblast-specific role of MRTF-A in renal fibrosis and the underlying mechanism. We report that myofibroblast-specific deletion of MRTF-A, achieved through crossbreeding Mrtfa-flox mice with Postn-Cre(ERT2) mice, led to amelioration of renal fibrosis. RNA-seq identified zinc finger E-Box binding homeobox 1 (Zeb1) as a downstream target of MRTF-A in renal fibroblasts. MRTF-A interacts with TEA domain transcription factor 1 (TEAD1) to bind to the Zeb1 promoter and activate Zeb1 transcription. Zeb1 knockdown retarded the fibroblast-myofibroblast transition (FMyT) in vitro and dampened renal fibrosis in mice. Transcriptomic assays showed that Zeb1 might contribute to FMyT by repressing the transcription of interferon regulatory factor 9 (IRF9). IRF9 knockdown overcame the effect of Zeb1 depletion and promoted FMyT, whereas IRF9 overexpression antagonized TGF-beta-induced FMyT. In conclusion, our data unveil a novel MRTF-A-Zeb1-IRF9 axis that can potentially contribute to fibroblast-myofibroblast transition and renal fibrosis. Screening for small-molecule compounds that target this axis may yield therapeutic options for the mollification of renal fibrosis. Kidney disease: Pathway to potential treatments for renal fibrosisTargeting a signalling pathway involving several proteins could help treat renal fibrosis in chronic kidney disease. Renal fibrosis, regulated by a network of transcription factors, involves the accumulation of extracellular matrix proteins in the kidneys and significantly affects kidney function and prognosis of kidney diseases. Previous studies have revealed that loss of myocardin-related transcription factor A (MRTF-A) reduces renal fibrosis. Investigators in China led by Tao Zhang, Nanjing Medical University, and Xiaoyan Wu, Nanjing Sports Institute, explored the specific role of MRFT-A in myofibroblasts. Using a novel transgenic mouse strain in which MRTF-A was deleted from myofibroblasts, these investigators found that MRTF-A might rely on a transcriptional cascade consisting of ZEB1 and IRF9 to drive renal fibrosis. Targeting individual components of this axis may yield novel therapeutics for the treatment of renal fibrosis.

Automated summary

This study found that myofibroblasts play an important role in renal fibrosis. By deleting myocardin-related transcription factor A (MRTF-A), the researchers discovered that MRTF-A promotes renal fibrosis by activating the transcription of Zeb1 and IRF9. These findings reveal a potential pathway for treating renal fibrosis.