Abstract
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.
Highlights
Acute kidney injury (AKI) is an extremely lifethreatening clinical syndrome characterized by a rapid decrease in renal function
We demonstrated that Rictor/ mammalian target of rapamycin complex 2 (mTORC2) signaling is crucial for protecting against renal inflammation and lipopolysaccharide (LPS)-induced AKI through inhibiting Yap/Taz degradation and NF-κB nuclear translocation
LPS activates Rictor/mTORC2 signaling in tubular cells Tubulointerstitial inflammation is the main characteristic of sepsis-induced AKI19
Summary
Acute kidney injury (AKI) is an extremely lifethreatening clinical syndrome characterized by a rapid decrease in renal function. Accumulated evidence unveils that tubular cells play important roles in AKI-related inflammation. Tubular cells are always the initial site of injury caused by hypoxia or ischemia, which in turn secretes inflammatory mediators and recruits inflammatory cells infiltration, exacerbating renal injury[1,2,3,4]. The mechanisms by which tubular cells trigger kidney inflammation remain unclear. MST1/2, SAV1, LATS1/2, MOB1A/B, Yes-associated protein (YAP) and its paralogue TAZ ( known as WWTR1) consist of the core components of the Hippo pathway. YAP and TAZ are the key downstream effectors of the Hippo pathway via MST1 and LATS kinases phosphorylation[5,6,7,8]
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