STAT3 signaling mediates peritoneal fibrosis by activating hyperglycolysis

Long term peritoneal dialysis leads to peritoneal epithelial-mesenchymal transformation (EMT), angiogenesis, and ultrafiltration failure. Although recent evidence suggests that inhibiting STAT3 (signal transducer and activator of transcription 3) can prevent kidney fibrosis, and that STAT3 can enhance glucose metabolism, the effect of STAT3 in peritoneal fibrosis (PF) has not been clarified.

Our study determined the effects of STAT3 on EMT and key glycolysis enzymes in mesothelial HMrSV5 cells by knockdown and overexpression of STAT3. In addition, we established a rat PF model to examine the role of pharmacologic inhibition of STAT3 or 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 (PFKFB3) in this process.

High glucose (HG) caused the upregulation of α-smooth muscle actin and transforming growth factor beta 1 and the downregulation of E-cadherin, and induced STAT3 activation in HMrSV5 cells. In addition, HMrSV5 cells cultured in high glucose showed high expression of key glycolysis enzymes, which could be inhibited by STAT3 siRNA. Furthermore, treating mesothelial cells with 3PO, the PFKFB3 inhibitor, could attenuate high glucose-induced EMT. Moreover, daily administration of dialysis fluid could induce peritoneal fibrosis. The peritoneal fibrosis was accompanied by enhanced phosphorylation of STAT3 and the upregulation of PFKFB3. The administration of BP-1-102 or 3PO prevented fibrosis and inhibited angiogenesis in PF rats.

si-STAT3 attenuated the HG-induced EMT and hyperglycolysis, and the overexpression of STAT3 could induce EMT in HMrSV5 cells. 3PO could markedly attenuate HG-induced EMT by decreasing PFKEB3 in HMrSV5 cells. In addition, we demonstrated that inhibiting STAT3 signaling or peritoneal hyperglycolysis could attenuate peritoneal fibrosis and angiogenesis in vivo. Our findings linked the STAT3/PFKFB3 signaling to the development of PF. HG/STAT3/PFKFB3 might promote the progression of PF through regulating profibrosis and angiogenesis.