Rapamycin attenuates PLA2R activation-mediated podocyte apoptosis via the PI3K/AKT/mTOR pathway
Rapamycin attenuates PLA2R activation-mediated podocyte apoptosis via the PI3K/AKT/mTOR pathway
复制标题
雷帕霉素通过PI 3 K/AKT/mTOR途径减弱PLA 2 R激活介导的足细胞凋亡
DOI：
10.1016/j.biopha.2021.112349
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发表时间：
2021-10-23
影响因子：
7.5
通讯作者：
Lee, Wen-Chin
中科院分区：
文献类型：
--
作者：
Chiou, Terry Ting-Yu;Chau, You-Ying;Lee, Wen-Chin
膜性肾病（MN）是非糖尿病成人肾病综合征的最常见原因。原发性 MN 与针对天然足细胞抗原的循环抗体有关，包括磷脂酶 A2 受体 (PLA2R)；然而，缺乏针对 PLA2R 激活信号级联的精准治疗。 PLA2R 和哺乳动物雷帕霉素靶蛋白 (mTOR) 均存在于足细胞中，但这两种蛋白之间的相互作用及其在 MN 中的作用值得进一步探索。本研究旨在研究人类足细胞系中 PLA2R 激活和 mTOR 信号传导之间的串扰。我们证明，足细胞凋亡是由 IB 族分泌性磷脂酶 A2 (sPLA2IB) 通过上调磷酸肌醇 3-激酶 (PI3K)、蛋白激酶 B (AKT) 和 mTOR 以浓度和时间依赖性方式诱导的，并被雷帕霉素或 LY294002 抑制。此外，PI3K/AKT/mTOR 通路的异常激活会触发足细胞中的外在（caspase-8 和 caspase-3）和内在（Bcl-2 相关 X 蛋白 [BAX]、B 细胞淋巴瘤 2 [BCL-2]、细胞色素 c、caspase-9 和 caspase-3）凋亡级联。我们的研究结果的治疗意义是，减少 PLA2R 激活的足细胞中 PLA2R 激活和 PI3K/AKT/mTOR 通路抑制的策略有助于保护足细胞免于凋亡。本研究显示的雷帕霉素的治疗潜力提供了支持雷帕霉素重新用于 MN 治疗的细胞证据。
Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults without diabetes. Primary MN has been associated with circulating antibodies against native podocyte antigens, including phospholipase A2 receptor (PLA2R); however, precision therapy targeting the signaling cascade of PLA2R activation is lacking. Both PLA2R and the mammalian target of rapamycin (mTOR) exist in podocytes, but the interplay between these two proteins and their roles in MN warrants further exploration. This study aimed to investigate the crosstalk between PLA2R activation and mTOR signaling in a human podocyte cell line. We demonstrated that podocyte apoptosis was induced by Group IB secretory phospholipase A2 (sPLA2IB) in a concentration-and time-dependent manner via upregulation of phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and mTOR, and inhibited by rapamycin or LY294002. Furthermore, aberrant activation of the PI3K/AKT/mTOR pathway triggers both extrinsic (caspase-8 and caspase-3) and intrinsic (Bcl-2-associated X protein [BAX], B-cell lymphoma 2 [BCL-2], cytochrome c, caspase-9, and caspase-3) apoptotic cascades in podocytes. The therapeutic implications of our findings are that strategies to reduce PLA2R activation and PI3K/AKT/mTOR pathway inhibition in PLA2R-activated podocytes help protect podocytes from apoptosis. The therapeutic potential of rapamycin shown in this study provides cellular evidence supporting the repurposing of rapamycin for MN treatment.