The Role And Mechanism Of MDM2 Membrane Translocation In Cisplatin-induced Acute Kidney Injury To Chronic Kidney Disease Transition

Cisplatin(CP),is a commonly used chemotherapy drug,however,its nephrotoxicity limits the clinical application.Low-dose and several cycles of CP treatment may promote acute kidney injury(AKI)to chronic kidney disease(CKD)transition,but the mechanism is not clear.Our previous study found that murine double minute 2(MDM2),an E3 ubiquitin ligase,is involved in tubulointerstitial fibrosis by mediating fibroblast activation.However,whether MDM2 is implicated in AKI-CKD transition remains unclear.To test whether MDM2 is involved in the progress of AKI to CKD,we established repeated low-dose CP-induced AKI-CKD transition model in vivo and in vitro.We confirmed that MDM2 is transported from nucleus to cell membrane in cortical tubules of AKI-CKD mice and in multiple CP-treated tubular epithelial cells(TECs).Importantly,overexpression of MDM2 in membrane significantly promotes AKI-CKD transition,whereas actinomycin D,a potent transcription inhibitor,can inhibit MDM2 membrane translocation and the development of AKI to CKD.We then analyzed downstream signaling of MDM2 membrane translocation during AKI-CKD transition.Firstly,we found that repeated CP administration results in nuclear p53 enhancement and G2/M arrest in TECs.On the other hand,multiple CP treatment promotes integrin β8 degradation and transforming growth factor-β1(TGF-β1)activation,and the activation of TGF-β1 can be negatively regulated by integrin β8.More interestingly,anchoring MDM2 on cell membrane can mimic the reduction of integrin β8arousing by repeated CP exposure.Collectively,our findings provide the first evidence that MDM2 membrane translocation is involved in AKI-CKD transition,which associates with nuclear p53 accumulation with ensuing G2/M arrest and membranous integrin β8 related TGF-β1 activation.Thus,the intervention of MDM2 membrane translocation may be an attractive target for reversion of AKI-CKD transition.