Our previous study demonstrated that the mammalian target of rapamycin complex 2 (mTORC2) signaling alleviates renal inflammation and protects against cisplatin-induced AKI. However, the underlying mechanisms for mTORC2 in regulating renal inflammation in AKI remain to be determined. In this study, we found that lipopolysaccharide (LPS) could activate mTORC2 signaling in NRK-52E cells, and blockage of mTORC2 signaling led to Yap/Taz degradation, which in turn activated NF-κB signaling and induced inflammatory cytokines secretion. Overexpression of constitutively active Taz (Taz-S89A) could attenuate the inflammation-amplified role of mTORC2 blockage. In mouse models, tubule-specific deletion of Rictor had higher blood urea nitrogen level, severe morphological injury as well as more inflammatory cells accumulation compared with those in their littermate controls. Overall, these results demonstrate that mTORC2 signaling protects against renal inflammation and dictates the outcome of AKI by modulating Yap/Taz degradation.

我们之前的研究表明，哺乳动物靶标雷帕霉素复合物 2 (mTORC2) 信号传导可减轻肾脏炎症并预防顺铂诱导的 AKI。然而，mTORC2 调节 AKI 肾脏炎症的潜在机制仍有待确定。在本研究中，我们发现脂多糖（LPS）可以激活NRK-52E细胞中的mTORC2信号传导，而mTORC2信号传导的阻断导致Yap/Taz降解，进而激活NF-κB信号传导并诱导炎症细胞因子的分泌。组成型活性 Taz (Taz-S89A) 的过表达可以减弱 mTORC2 阻断的炎症放大作用。在小鼠模型中，与同窝对照小鼠相比，Rictor 的肾小管特异性缺失具有更高的血液尿素氮水平、严重的形态损伤以及更多的炎症细胞积累。总体而言，这些结果表明 mTORC2 信号传导可预防肾脏炎症，并通过调节 Yap/Taz 降解来决定 AKI 的结果。