Dapagliflozin delays renal fibrosis in diabetic kidney disease by inhibiting YAP/TAZ activation

Abstract

In diabetic kidney disease (DKD), the long-term hyperactivation of yes-associated protein (YAP)/transcriptional coactivator PDZ-binding motif (TAZ) in renal proximal tubule epithelial cells (RPTCs) plays an important role in progressive tubulointerstitial fibrosis. Sodium-glucose cotransporter 2 (SGLT2) is highly expressed in RPTCs, but its relationship with YAP/TAZ in tubulointerstitial fibrosis in DKD is still unknown. The purpose of this study was to clarify whether the SGLT2 inhibitor (SGLT2i) dapagliflozin could alleviate renal tubulointerstitial fibrosis in DKD by regulating YAP/TAZ. We examined 58 patients with DKD confirmed by renal biopsy and found that the expression and nuclear translocation of YAP/TAZ increased with the exacerbation of chronic kidney disease classification. In models of DKD, dapagliflozin showed similar effects to verteporfin, an inhibitor of YAP/TAZ, in reducing the activation of YAP/TAZ and downregulating the expression of their target genes, connective tissue growth factor (CTGF) and amphiregulin in vivo and in vitro. Silencing SGLT2 also confirmed this effect. Importantly, dapagliflozin showed a better effect than verteporfin in inhibiting inflammation, oxidative stress and fibrosis in the kidney in DKD rats. Taken together, this study proved for the first time that dapagliflozin delayed tubulointerstitial fibrosis at least partly by inhibiting YAP/TAZ activation, which further enriched the antifibrotic effect of SGLT2i.