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Published on: June 27, 2017
STAT3 signaling mediates peritoneal fibrosis by activating hyperglycolysis
Jiao Fu1, Nan Li1, Mengmeng He1
1Department of Nephrology, The First Affiliated Hospital of Anhui Medical University Hefei 230032, Anhui, P.R. China.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Insights
Inhibiting STAT3 signaling or hyperglycolysis reduces peritoneal fibrosis and angiogenesis. This study links STAT3/PFKFB3 signaling to peritoneal fibrosis progression in high glucose conditions.
Area of Science:
- Nephrology
- Cell Biology
- Molecular Biology
Background:
- Long-term peritoneal dialysis can cause peritoneal epithelial-mesenchymal transformation (EMT), angiogenesis, and ultrafiltration failure.
- STAT3 inhibition may prevent kidney fibrosis and enhance glucose metabolism, but its role in peritoneal fibrosis (PF) is unclear.
Purpose of the Study:
- To investigate the effects of STAT3 on EMT and glycolysis in mesothelial cells.
- To determine the role of STAT3 and PFKFB3 inhibition in a rat model of peritoneal fibrosis.
Main Methods:
- STAT3 knockdown and overexpression in HMrSV5 cells.
- Establishment of a rat PF model.
- Pharmacologic inhibition of STAT3 and PFKFB3.
Main Results:
- High glucose induced EMT, STAT3 activation, and upregulation of glycolysis enzymes in HMrSV5 cells.
- STAT3 inhibition or PFKFB3 inhibition (3PO) attenuated high glucose-induced EMT.
- Inhibition of STAT3 or PFKFB3 in rats prevented peritoneal fibrosis and angiogenesis.
Conclusions:
- STAT3/PFKFB3 signaling is linked to peritoneal fibrosis development.
- Inhibiting STAT3 or peritoneal hyperglycolysis can attenuate PF and angiogenesis.
- High glucose, STAT3, and PFKFB3 may drive PF progression via profibrosis and angiogenesis.
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