Department of Microbiology and Immunology, Showa University School of Medicine, Tokyo, Japan.
Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
Sci Rep. 2023 Feb 1;13(1):1867. doi: 10.1038/s41598-023-29161-3.
Hypoxia-inducible factor-prolyl hydroxylase (HIF-PHD) inhibitors are therapeutic agents for renal anemia that work through HIF2-mediated upregulation of erythropoietin (EPO) and have also been reported to suppress renal fibrosis. Group 2 innate lymphoid cells (ILC2s) have been proven to be involved in the pathogenesis of fibrosis in various organs, including the kidney. However, the relationship between the HIF pathway, renal fibrosis, and kidney ILC2s remains unclear. In the present study, we found that HIF activation by HIF-PHD inhibitors suppressed type 2 cytokine production from kidney ILC2s. The enhanced HIF pathway downregulated the IL-33 receptor ST2L on ILC2s, and phosphorylation of downstream p38 MAPK was attenuated. M2 macrophages that promote renal fibrosis were polarized by ILC2 supernatants, but reduced cytokine production from ILC2s treated with HIF-PHD inhibitors suppressed this polarization. Our findings suggest that HIF-PHD inhibitors are potential therapeutic agents for renal fibrosis that are mediated by the alteration of ILC2 function.
缺氧诱导因子脯氨酰羟化酶（HIF-PHD）抑制剂是治疗肾性贫血的药物，通过 HIF2 介导的促红细胞生成素（EPO）上调起作用，并且据报道还能抑制肾纤维化。2 型固有淋巴细胞（ILC2）已被证明参与各种器官（包括肾脏）的纤维化发病机制。然而，HIF 通路、肾纤维化和肾脏 ILC2 之间的关系尚不清楚。在本研究中，我们发现 HIF-PHD 抑制剂通过激活 HIF 抑制了肾脏 ILC2 中 2 型细胞因子的产生。增强的 HIF 通路下调了 ILC2 上的 IL-33 受体 ST2L，并且下游 p38 MAPK 的磷酸化减弱。ILC2 上清液可极化促进肾纤维化的 M2 巨噬细胞，但用 HIF-PHD 抑制剂处理的 ILC2 减少细胞因子的产生抑制了这种极化。我们的研究结果表明，HIF-PHD 抑制剂是通过改变 ILC2 功能介导的肾纤维化的潜在治疗药物。
