Center for Kidney Disease, the 2nd Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
Department of Clinical Genetics, the 2nd Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
Cell Death Differ. 2021 Sep;28(9):2728-2744. doi: 10.1038/s41418-021-00780-5. Epub 2021 May 1.
Macrophage accumulation and activation play an essential role in kidney fibrosis; however, the underlying mechanisms remain to be explored. By analyzing the kidney tissues from patients and animal models with kidney fibrosis, we found a large induction of PP2Acα in macrophages. We then generated a mouse model with inducible macrophage ablation of PP2Acα. The knockouts developed less renal fibrosis, macrophage accumulation, or tubular cell death after unilateral ureter obstruction or ischemic reperfusion injury compared to control littermates. In cultured macrophages, PP2Acα deficiency resulted in decreased cell motility by inhibiting Rap1 activity. Moreover, co-culture of PP2Acα macrophages with tubular cells resulted in less tubular cell death attributed to downregulated Stat6-mediated tumor necrosis factor α (TNFα) production in macrophages. Together, this study demonstrates that PP2Acα promotes macrophage accumulation and activation, hence accelerates tubular cell death and kidney fibrosis through regulating Rap1 activation and TNFα production.
巨噬细胞的积累和激活在肾纤维化中起着至关重要的作用；然而，其潜在机制仍有待探索。通过分析肾纤维化患者和动物模型的肾脏组织，我们发现巨噬细胞中 PP2Acα 的大量诱导。然后，我们生成了一种可诱导巨噬细胞中 PP2Acα 缺失的小鼠模型。与对照同窝仔相比，敲除小鼠在单侧输尿管梗阻或缺血再灌注损伤后肾纤维化、巨噬细胞积累或肾小管细胞死亡减少。在培养的巨噬细胞中，PP2Acα 缺乏通过抑制 Rap1 活性导致细胞迁移减少。此外，PP2Acα 巨噬细胞与肾小管细胞共培养导致肾小管细胞死亡减少，这归因于巨噬细胞中 Stat6 介导的肿瘤坏死因子 α (TNFα) 产生下调。总之，这项研究表明，PP2Acα 通过调节 Rap1 激活和 TNFα 产生促进巨噬细胞的积累和激活，从而加速肾小管细胞死亡和肾纤维化。
