Identification of YAP1 as a novel downstream effector of the FGF2/STAT3 pathway in the pathogenesis of renal tubulointerstitial fibrosis

Abstract

Chronic kidney disease is a global health problem and eventually develops into an end-stage renal disease (ESRD). It is now widely believed that renal tubulointerstitial fibrosis (TIF) plays an important role in the progression of ESRD. Renal tubular epithelial-mesenchymal transition (EMT) is an important cause of TIF. Studies have shown that FGF2 is highly expressed in fibrotic renal tissue, although the mechanism remains unclear. We found that FGF2 can activate STAT3 and induce EMT in renal tubular epithelial cells. STAT3, an important transcription factor, was predicted by the JASPAR biological database to bind to the promoter region of YAP1. In this study, STAT3 was shown to promote the expression of the downstream target gene YAP1 through transcription, promote EMT of renal tubular epithelial cells, and mediate the occurrence of renal TIF. This study provides a theoretical basis for the involvement of the FGF2/STAT3/YAP1 signaling pathway in the process of renal interstitial fibrosis and provides a potential target for the treatment of renal fibrosis.epithelial-mesenchymal transition (EMT), fibroblast growth factor 2 (FGF2), renal tubulointerstitial fibrosis (TIF), signal transducer and activator of transcription 3 (STAT3), Yes-associated protein 1 (YAP1)

Tanshinone IIA attenuates high glucose-induced epithelial-to-mesenchymal transition in HK-2 cells through VDR/Wnt/β-catenin signaling pathway

“…In the past, DKD has been regarded as a disease mainly characterized by glomerular injury, and the role of renal tubular injury in DKD has been neglected; in recent years, more and more studies have revealed the importance of renal tubulointerstitial injury in the progression of DKD [15]. The main cause of tubulointerstitial fibrosis is renal tubular EMT [16,17]; therefore, the inhibition of EMT can alleviate tubulointerstitial fibrosis [18]. EMT is a collective name for a series of cellular biological process in which cells differentiate from epithelial cell phenotype into mesenchymal cells phenotype under specific physiological or pathological conditions [19].…”

YAP/TAZ: Molecular pathway and disease therapy

“…found that activation of both the EGFR/PI3K/Akt signaling pathway and the RhoA/Rock signaling pathway in diabetic renal proximal tubular epithelial cells promoted YAP activation and there was a crosstalk between these two signaling pathways. In addition to these signaling pathways, both FGF2/STAT3 and YTH domain‐containing protein family (YTHDF1) can also exacerbate renal fibrosis by upregulating YAP expression 307,308 . In conclusion, there are many YAP/TAZ signaling pathways involved in renal fibrosis, so exploring drugs that inhibit the activation of profibrotic YAP/TAZ signaling pathways may open the way for antifibrotic therapy.…”

“…In addition to these signaling pathways, both FGF2/STAT3 and YTH domain‐containing protein family (YTHDF1) can also exacerbate renal fibrosis by upregulating YAP expression. 307 , 308 In conclusion, there are many YAP/TAZ signaling pathways involved in renal fibrosis, so exploring drugs that inhibit the activation of profibrotic YAP/TAZ signaling pathways may open the way for antifibrotic therapy.…”

Role of SUMOylation of STAT1 in tubular epithelial‑mesenchymal transition induced by high glucose

“…Studies have shown that p-STaT1 and p-STaT3 are involved in EMT and subsequent TIF under several conditions (10)(11)(12)(13). The role of STaT3 in eMT and fibrosis has been widely recognized (14)(15)(16)(17)(18); however, other studies have suggested that the activation of STAT1 exhibits anti-fibrotic properties by reducing macrophage infiltration or changing the phenotype of macrophages in renal ischemia-reperfusion injury (19). Tumor-related studies have also demonstrated that the activation of STaT1 mediated the effect of interleukin-27 in reversing trophoblast cell eMT (20).…”