CCL18-PITPNM3 Mediates Macrophage-Mesothelial Cross-Talk and Promotes Peritoneal Dialysis-Associated Peritoneal Fibrosis
- Home Dialysis - II
November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
- 802 Dialysis: Home Dialysis and Peritoneal Dialysis
- Sun, Yuxiang, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- Huang, Qiang, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- Peng, Hui, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
Peritoneal dialysis (PD) is one of the replacement therapies for end-stage renal disease. After long-term PD(LPD) treatment, about 50% of patients will develop peritoneal fibrosis and ultrafiltration failure. Macrophages and metabolic reprogramming have been confirmed to play an important role in PD-related peritoneal fibrosiss.
We performed scRNA-seq on perfusate cells from patients receiving PD treatment and explored the functions of specific cell types in the development of PD-related peritoneal fibrosis. By cell communication analysis, we interrogated crosstalk among different cell types in PD effluent. Then we used western blot, qPCR and seahorse to investigate the downstream pathway.
We discovered that LPD promoted interactions between macrophages and mesothelial cells. We also found that LPD induced the M2 polarization of macrophages. CCL18 was identified to be the most significantly M2-type macrophage-secreted factor upregulated in LPD patients. Moreover, the increased concentration of CCL18 in the PD effluent of LPD patients was related to the high peritoneal transport. It was found that PITPNM3 was the most abundant and significantly elevated receptor for CCL18 in the mesothelial cells of LPD patients. Knocking down PITPNM3 receptor ameliorated EMT of mesothelial cells induced by CCL18. Finally, we discovered that CCL18-PITPNM3 could promote the expression of glycolysis enzyme HK2 by activating the PI3K-Akt-cMyc signaling pathway.
PD promoted macrophage M2 polarization and increase CCL18 secretion. CCL18 binds to PITPNM3 in mesothelial cells activating the PI3K/Akt/cMyc.HK2 signaling pathway, so as to enhance the glycolysis and EMT of mesothelial cells and lead to PD-related peritoneal fibrosis.