Liu Yexin, Leng Bin, Xia Ming, Liu Di, Tan Xia, Chen Guochun, He Liyu, Wang Chang, Zhu Xuejing, Liu Hong
Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha 410011.
Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha 410011, China.
Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2024 Aug 28;49(8):1220-1231. doi: 10.11817/j.issn.1672-7347.2024.240209.
IgA nephropathy (IgAN) is the most common primary glomerular disease in China, but its pathogenesis remains unclear. This study aims to explore the regulatory role of the mammalian target of rapamycin (mTOR) signaling pathway in autophagy and mesangial proliferation during renal injury in IgA.
The activity of mTOR and autophagy was evaluated in kidney samples from IgAN patients and in an IgAN mouse model induced by oral bovine serum albumin and carbon tetrachloride (CCl4) injection. mTOR inhibitors (rapamycin) and activators [bpV(phen)] were administered to the IgAN mouse model to observe the effects of mTOR on autophagy and renal lesions. In human mesangial cells treated with polymeric IgA1 (p-IgA1) and mTOR modulators, the expression and distribution of cell cycle proteins were assessed, along with the effects of mTOR on mesangial cell proliferation and autophagy.
Increased mTOR activity and decreased autophagy were observed in kidney tissues from IgAN patients and the mouse model, as evidenced by elevated phosphorylated mTOR (p-mTOR) levels and reduced LC3 expression. In the IgAN mouse model, rapamycin inhibited mTOR, restored autophagy, reduced mesangial IgA deposition, alleviated mesangial cell proliferation, and decreased proteinuria (all <0.05). In contrast, bpV(phen) activated mTOR, further suppressed autophagy, exacerbated kidney damage, and increased proteinuria (all <0.05). In vitro, p-IgA1 induced mesangial cell proliferation and inhibited autophagy, effects that were reversed by rapamycin and aggravated by bpV(phen) (all <0.05). mTOR regulated mesangial cell proliferation by altering cell cycle distribution, with rapamycin inducing G1 phase arrest and bpV(phen) promoting cell cycle progression. Additionally, cyclinD1 expression in renal cortex was up-regulated in the IgAN mouse model, further increased by bpV(phen), and reduced by rapamycin (all <0.05).
Inhibition of the mTOR signaling pathway enhances renal autophagy, reduces mesangial cell proliferation, and improves renal injury in IgAN.
IgA 肾病（IgAN）是中国最常见的原发性肾小球疾病，但其发病机制仍不清楚。本研究旨在探讨雷帕霉素靶蛋白（mTOR）信号通路在 IgA 肾病肾损伤过程中对自噬和系膜细胞增殖的调节作用。
在 IgAN 患者的肾组织样本以及通过口服牛血清白蛋白和注射四氯化碳（CCl4）诱导的 IgAN 小鼠模型中评估 mTOR 和自噬的活性。将 mTOR 抑制剂（雷帕霉素）和激活剂[bpV（phen）]给予 IgAN 小鼠模型，以观察 mTOR 对自噬和肾损伤的影响。在用聚合 IgA1（p-IgA1）和 mTOR 调节剂处理的人系膜细胞中，评估细胞周期蛋白的表达和分布，以及 mTOR 对系膜细胞增殖和自噬的影响。
在 IgAN 患者和小鼠模型的肾组织中观察到 mTOR 活性增加和自噬减少，磷酸化 mTOR（p-mTOR）水平升高和 LC3 表达降低证明了这一点。在 IgAN 小鼠模型中，雷帕霉素抑制 mTOR，恢复自噬，减少系膜 IgA 沉积，减轻系膜细胞增殖，并降低蛋白尿（均<0.05）。相反，bpV（phen）激活 mTOR，进一步抑制自噬，加重肾损伤，并增加蛋白尿（均<0.05）。在体外，p-IgA1 诱导系膜细胞增殖并抑制自噬，雷帕霉素可逆转这些作用，bpV（phen）则加剧这些作用（均<0.05）。mTOR 通过改变细胞周期分布来调节系膜细胞增殖，雷帕霉素诱导 G1 期阻滞，bpV（phen）促进细胞周期进程。此外，IgAN 小鼠模型肾皮质中细胞周期蛋白 D1 的表达上调，bpV（phen）使其进一步增加，雷帕霉素使其降低（均<0.05）。
抑制 mTOR 信号通路可增强肾自噬，减少系膜细胞增殖，并改善 IgAN 患者的肾损伤。
