Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China.
Cell Prolif. 2022 Sep;55(9):e13278. doi: 10.1111/cpr.13278. Epub 2022 Jun 22.
Mesangial cell proliferation is the most basic pathological feature of immunoglobulin A nephropathy (IgAN); however, the specific underlying mechanism and an appropriate therapeutic strategy are yet to be unearthed. This study aimed to investigate the therapeutic effect of triptolide (TP) on IgAN and the mechanism by which TP regulates autophagy and proliferation of mesangial cells through the CARD9/p38 MAPK pathway.
We established a TP-treated IgAN mouse model and produced IgA1-induced human mesangial cells (HMC) and divided them into control, TP, IgAN, and IgAN+TP groups. The levels of mesangial cell proliferation (PCNA, cyclin D1, cell viability, and cell cycle) and autophagy (P62, LC3 II, and autophagy flux rate) were measured, with the autophagy inhibitor 3-Methyladenine used to explore the relationship between autophagy and proliferation. We observed CARD9 expression in renal biopsies from patients and analyzed its clinical significance. CARD9 siRNA and overexpression plasmids were constructed to investigate the changes in mesangial cell proliferation and autophagy as well as the expression of CARD9 and p-p38 MAPK/p38 MAPK following TP treatment.
Administering TP was safe and effectively alleviated mesangial cell proliferation in IgAN mice. Moreover, TP inhibited IgA1-induced HMC proliferation by promoting autophagy. The high expression of CARD9 in IgAN patients was positively correlated with the severity of HMC proliferation. CARD9/p38 MAPK was involved in the regulation of HMC autophagy and proliferation, and TP promoted autophagy to inhibit HMC proliferation by downregulating the CARD9/p38 MAPK pathway in IgAN.
TP promotes autophagy to inhibit mesangial cell proliferation in IgAN via the CARD9/p38 MAPK pathway.
系膜细胞增殖是免疫球蛋白 A 肾病（IgAN）最基本的病理特征；然而，特定的潜在机制和适当的治疗策略尚未被发现。本研究旨在探讨雷公藤红素（TP）治疗 IgAN 的疗效，以及 TP 通过 CARD9/p38 MAPK 通路调节系膜细胞自噬和增殖的机制。
我们建立了 TP 治疗的 IgAN 小鼠模型，并产生了 IgA1 诱导的人系膜细胞（HMC），并将其分为对照组、TP 组、IgAN 组和 IgAN+TP 组。测量系膜细胞增殖（PCNA、细胞周期蛋白 D1、细胞活力和细胞周期）和自噬（P62、LC3 II 和自噬通量率）的水平，并用自噬抑制剂 3-甲基腺嘌呤来探讨自噬与增殖的关系。我们观察了患者肾活检中的 CARD9 表达，并分析了其临床意义。构建了 CARD9 siRNA 和过表达质粒，以研究 TP 处理后系膜细胞增殖和自噬的变化，以及 CARD9 和 p-p38 MAPK/p38 MAPK 的表达。
给予 TP 是安全有效的，可缓解 IgAN 小鼠系膜细胞增殖。此外，TP 通过促进自噬抑制 IgA1 诱导的 HMC 增殖。IgAN 患者中 CARD9 的高表达与 HMC 增殖的严重程度呈正相关。CARD9/p38 MAPK 参与调节 HMC 自噬和增殖，TP 通过下调 IgAN 中的 CARD9/p38 MAPK 通路促进自噬抑制 HMC 增殖。
TP 通过 CARD9/p38 MAPK 通路促进自噬抑制 IgAN 中的系膜细胞增殖。
