Wang Qing, Chen Xiaolong, Huang Kunyuan, Deng Guanyun, Tian Yuan, Jiang Kehua
Department of Urology, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550000, China.
Department of Urology, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550000, China.
Int J Biol Macromol. 2024 Nov;281(Pt 1):136178. doi: 10.1016/j.ijbiomac.2024.136178. Epub 2024 Sep 30.
To explore the role of S100A9 protein in renal calcium oxalate (CaOx) stone formation.
CaOx nephrocalcinosis mice were established via intraperitoneal injection of glyoxylate. They were treated with S100A9 deficiency, Paquinimod, or p38 MAPK-IN-1. Vonkossa staining was conducted to observe the deposition of CaOx crystals. Renal expression of inflammation, macrophage polarization, and injury markers was detected using immunohistochemistry and qPCR. Effects of S100A9 on renal tubular epithelial cells (HK-2) were explored by transcriptome sequencing. The mechanism of how S100A9 regulated lipocalin 2 (LCN2) was studied through Western Blot. Flow cytometry was performed to detect the influence of LCN2 on macrophages polarization.
S100A9 deficiency inhibited the renal deposition of CaOx crystals in nephrocalcinosis mice. S100A9 upregulated the expression of LCN2 in HK-2 cells via activating the TLR4-p38/MAPK pathway. LCN2 promoted the migration and M1 polarization of macrophages. S100A9 deficiency downregulated the renal expression of LCN2, IL1-β, Kim-1, F4/80, and CD80 in nephrocalcinosis mice. Paquinimod and p38 MAPK-IN-1 both inhibited the renal deposition of CaOx crystals and downregulated the expression of LCN2, IL1-β, Kim-1, F4/80, iNOS, and CD68 in nephrocalcinosis mice.
S100A9 promotes renal inflammatory injury by activating the TLR4-p38/MAPK-LCN2 pathway and then contributes to CaOx stone formation.
探讨S100A9蛋白在肾草酸钙（CaOx）结石形成中的作用。
通过腹腔注射乙醛酸建立CaOx肾钙沉着症小鼠模型。分别用S100A9基因缺陷、帕喹莫德或p38丝裂原活化蛋白激酶抑制剂-1（p38 MAPK-IN-1）对其进行处理。采用冯科萨染色观察CaOx晶体的沉积情况。运用免疫组织化学和定量聚合酶链反应检测肾脏中炎症、巨噬细胞极化和损伤标志物的表达。通过转录组测序探究S100A9对肾小管上皮细胞（HK-2）的影响。采用蛋白质免疫印迹法研究S100A9调节脂质运载蛋白2（LCN2）的机制。运用流式细胞术检测LCN2对巨噬细胞极化的影响。
S100A9基因缺陷抑制了肾钙沉着症小鼠肾脏中CaOx晶体的沉积。S100A9通过激活Toll样受体4（TLR4）-p38/丝裂原活化蛋白激酶（MAPK）途径上调HK-2细胞中LCN2的表达。LCN2促进巨噬细胞的迁移和M1极化。S100A9基因缺陷下调了肾钙沉着症小鼠肾脏中LCN2、白细胞介素-1β（IL1-β）、肾损伤分子-1（Kim-1）、F4/80和分化簇80（CD80）的表达。帕喹莫德和p38 MAPK-IN-1均抑制了肾钙沉着症小鼠肾脏中CaOx晶体的沉积，并下调了LCN2、IL1-β、Kim-1、F4/80、诱导型一氧化氮合酶（iNOS）和分化簇68（CD68）的表达。
S100A9通过激活TLR4-p38/MAPK-LCN2途径促进肾脏炎性损伤，进而促进CaOx结石形成。
