Department of Nephrology, the First Affiliated Hospital of Hainan Medical University, Haikou, China.
Department of Orthopedics, the First Affiliated Hospital of Hainan Medical University, Haikou, China.
PLoS One. 2020 Mar 5;15(3):e0228385. doi: 10.1371/journal.pone.0228385. eCollection 2020.
Our earlier studies proved that RIPK3-mediated necroptosis might be an important mode of renal tubular cell death in rats with chronic renal injury and the necroptotic cell death can be triggered by tumor necrosis factor-α (TNF-α) in vitro, but the triggering role of angiotensin II (AngII), which exerts notable effects on renal cells for the initiation and progression of renal tubulointerstitial fibrosis, is largely unknown. Here, we identified the presence of necroptotic cell death in the tubular cells of AngII-induced chronic renal injury and fibrosis mice and assessed the percentage of necroptotic renal tubular cell death with the disruption of this necroptosis by the addition of necrostatin-1 (Nec-1). Furthermore, the observation was further confirmed in HK-2 cells treated with AngII and RIPK1/3 or MLKL inhibitors. The detection of Fas and FasL proteins led us to investigate the contribution of the Fas/FasL signaling pathway to AngII-induced necroptosis. Disruption of FasL decreased the percentage of necroptotic cells, suggesting that Fas and FasL are likely key signal molecules in the necroptosis of HK-2 cells induced by AngII. Our data suggest that AngII exposure might trigger RIPK3-MLKL-mediated necroptosis in renal tubular epithelial cells by activating the Fas/FasL signaling pathway in vivo and in vitro.
我们之前的研究证明 RIPK3 介导的坏死可能是慢性肾损伤大鼠肾小管细胞死亡的一种重要方式，体外 TNF-α（肿瘤坏死因子-α）可以触发坏死性细胞死亡，但血管紧张素 II（AngII）的触发作用在很大程度上是未知的，AngII 对肾细胞具有显著作用，可引发和促进肾间质纤维化。在这里，我们在 AngII 诱导的慢性肾损伤和纤维化小鼠的肾小管细胞中鉴定出坏死性细胞死亡的存在，并通过添加坏死抑制剂-1（Nec-1）破坏这种坏死来评估坏死性肾小管细胞死亡的百分比。此外，还在 AngII 和 RIPK1/3 或 MLKL 抑制剂处理的 HK-2 细胞中进一步观察到这种现象。 Fas 和 FasL 蛋白的检测使我们研究了 Fas/FasL 信号通路对 AngII 诱导的坏死的贡献。FasL 的破坏减少了坏死性细胞的百分比，表明 Fas 和 FasL 可能是 AngII 诱导的 HK-2 细胞坏死的关键信号分子。我们的数据表明，AngII 暴露可能通过体内和体外激活 Fas/FasL 信号通路，在肾小管上皮细胞中触发 RIPK3-MLKL 介导的坏死。
