Deletion of p38 MAPK in macrophages ameliorates peritoneal fibrosis and inflammation in peritoneal dialysis

• Published in: Scientific reports 2024-09, Vol.14 (1), p.21220-12, Article 21220
• Main Authors: Ikushima, Akie, Ishimura, Takuya, Mori, Keita P., Yamada, Hiroyuki, Sugioka, Sayaka, Ishii, Akira, Toda, Naohiro, Ohno, Shoko, Kato, Yukiko, Handa, Takaya, Yanagita, Motoko, Yokoi, Hideki
• Format: Article
• Language: English
• Subjects: 692/4022/1585; 692/4022/1950; Animals; Chlorhexidine; Chlorhexidine - analogs & derivatives; Chlorhexidine - pharmacology; Dialysis; Fibrosis; Gene expression; Humanities and Social Sciences; Humans; Inflammation; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Lipopolysaccharides; Macrophage; Macrophages; Macrophages - metabolism; Male; MAP kinase; Mice; Mice, Knockout; multidisciplinary; p38 MAPK; p38 Mitogen-Activated Protein Kinases - metabolism; Peritoneal dialysis; Peritoneal Dialysis - adverse effects; Peritoneal Fibrosis - etiology; Peritoneal Fibrosis - genetics; Peritoneal Fibrosis - metabolism; Peritoneal Fibrosis - pathology; Peritoneum; Peritoneum - pathology; RAW 264.7 Cells; Science; Science (multidisciplinary); Ultrafiltration
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-71859-5

One of the most common causes of peritoneal dialysis withdrawal is ultrafiltration failure which is characterized by peritoneal membrane thickening and fibrosis. Although previous studies have demonstrated the inhibitory effect of p38 MAPK inhibitors on peritoneal fibrosis in mice, it was unclear which specific cells contribute to peritoneal fibrosis. To investigate the role of p38 MAPK in peritoneal fibrosis more precisely, we examined the expression of p38 MAPK in human peritoneum and generated systemic inducible p38 MAPK knockout mice and macrophage-specific p38 MAPK knockout mice. Furthermore, the response to lipopolysaccharide (LPS) was assessed in p38 MAPK-knocked down RAW 264.7 cells to further explore the role of p38 MAPK in macrophages. We found that phosphorylated p38 MAPK levels were increased in the thickened peritoneum of both human and mice. Both chlorhexidine gluconate (CG)-treated systemic inducible and macrophage-specific p38 MAPK knockout mice ameliorated peritoneal thickening, mRNA expression related to inflammation and fibrosis, and the number of αSMA- and MAC-2-positive cells in the peritoneum compared to CG control mice. Reduction of p38 MAPK in RAW 264.7 cells suppressed inflammatory mRNA expression induced by LPS. These findings suggest that p38 MAPK in macrophages plays a critical role in peritoneal inflammation and thickening.