Abstract: SA-PO948
Valsartan Ameliorates High Glucose-Induced Peritoneal Fibrosis by Blocking mTORC1 Signaling
Session Information
- Peritoneal Dialysis: Inflammation, Peritoneal Transport
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Dialysis
- 703 Dialysis: Peritoneal Dialysis
Author
- Jing, Liu, Institute of Nephrology, Nanjing City, Jiangsu, China
Background
Increasing evidences suggest that angiotensin II type 1 receptor (AT1R) blockers prevent peritoneal fibrosis (PF) under high glucose (HG) conditions. The study aimed to investigate the undefined mechanisms by which AT1R blocker valsartan on HG induced PF.
Methods
We used HG peritoneal dialysis solution (PDS) in a mouse peritoneal dialysis model to induce in vivo PF and HG in human peritoneal mesothelial cells (HPMCs) in vitro to stimulate extracellular matrix (ECM) accumulation.
Results
After the injection of 4.25% PDS for 4 weeks, mice showed typical features of PF, including markedly increased peritoneal thickness, excessive matrix deposition, increased peritoneal permeability, and higher expressions of ECM markers, such as α-smooth muscle actin (α-SMA) and collagen I. Valsartan significantly ameliorated these pathological changes at either week 6 or 8. These effects of valsartan were closely correlated with a decrease in the activation of mammalian target of rapamycin complex 1 (mTORC1) pathway, which was mediated through the down-regulation of protein expressions of phosphorylated-mTOR (p-mTOR), p-eukaryotic initiation factor 4E-binding protein 1 (p-4EBP1), and P-p70 S6 kinase (p-S6K1). Further analysis showed the protein expression of p-mTOR, p-4EBP1, p-S6K1 was positively correlated with the expression of either α-SMA or collagen I in the peritoneum. In vitro, HG increased the protein expressions of α-SMA and collagen I in a dose dependent manner, while valsartan significantly inhibited HG-induced ECM accumulation in HPMCs. The effect was also accompanied by a decrease in the activation of mTORC1 pathway. Furthermore, mTOR agonist-MHY1485 could reverse the downregulation of ECM components in HPMCs, even in the presence of valsartan.
Conclusion
We conclude that valsartan shows a protective effect on HG-induced PF by inhibiting the activity of mTORC1 pathway.
Funding
- Other NIH Support