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巨噬细胞中 p38MAPK 的缺失可改善腹膜透析中的腹膜纤维化和炎症。

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

机构信息

Department of Nephrology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Kyoto, 6068507, Japan.

Department of Nephrology and Dialysis, Medical Research Institute KITANO HOSPITAL, PIIF Tazuke-Kofukai, Osaka, Japan.

出版信息

Sci Rep. 2024 Sep 11;14(1):21220. doi: 10.1038/s41598-024-71859-5.

DOI:10.1038/s41598-024-71859-5
PMID:39261560
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11391064/
Abstract

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.

摘要

超滤衰竭是腹膜透析退出的最常见原因之一，其特征为腹膜膜增厚和纤维化。虽然先前的研究已经证明了 p38MAPK 抑制剂对小鼠腹膜纤维化的抑制作用，但尚不清楚哪种特定细胞对腹膜纤维化有贡献。为了更精确地研究 p38MAPK 在腹膜纤维化中的作用，我们检查了人腹膜中 p38MAPK 的表达，并生成了全身性诱导型 p38MAPK 敲除小鼠和巨噬细胞特异性 p38MAPK 敲除小鼠。此外，我们还在 p38MAPK 敲低的 RAW264.7 细胞中评估了脂多糖（LPS）的反应，以进一步探讨 p38MAPK 在巨噬细胞中的作用。我们发现，人腹膜和小鼠腹膜增厚部位的磷酸化 p38MAPK 水平均升高。与 CG 对照小鼠相比，用洗必泰葡萄糖酸盐（CG）处理的全身性诱导型和巨噬细胞特异性 p38MAPK 敲除小鼠均改善了腹膜增厚、与炎症和纤维化相关的 mRNA 表达以及腹膜中 αSMA-和 MAC-2 阳性细胞的数量。RAW264.7 细胞中 p38MAPK 的减少抑制了 LPS 诱导的炎症 mRNA 表达。这些发现表明，巨噬细胞中的 p38MAPK 在腹膜炎症和增厚中起关键作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1e7/11391064/df1281888509/41598_2024_71859_Fig7_HTML.jpg
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