The Role And Mechanism Of PTEN In Acute Kidney Injury And AKI To CKD Transition

BackgroundPhosphatase and Tensin Homologue on chromosome Ten(PTEN),the unique tumor suppressor possessing double-specific phosphatase activity so far,involves in a variety of biological processes.Acute kidney injury(AKI)is a syndrome defined by rapid loss of renal function.Notably,AKI can trigger immediate kidney damage(referred to as acute kidney disease,AKD)or long-term damage(in the form of chronic kidney disease,CKD,and end-stage renal disease,ESRD),both due to maladaptive repair.We previously demonstrated that podocyte-specific PTEN knock-in alleviated urinary albumin and glomerular sclerosis in mice subjected to DKD.Although PTEN has emerged as a key protein that governs the response to kidney injury,whether and how PTEN works in renal acute injury and maladaptive repair remains unclear.MethodsIschemia/reperfusion(I/R)was conducted to induce acute kidney injury and renal maladaptive repair in mice.Renal proximal tubular cells(RPTC)-specific PTEN overexpression mice were established by crossing PTENfl-stop-fl mice with Ggtl-Cre mice via Cre-loxP system.Mass spectrometry-based proteomics was performed after subjecting these mice to ischemia/reperfusion(I/R).In addition,ATP/glucose depletion was used to establish I/R-induced cultured HK-2 injury model.ResultsWe found that PTEN was downregulated in renal tubular cells in mice and cultured HK-2 subjected to renal acute injury and maladaptive repair induced by I/R.Renal expression of PTEN negatively correlated with NGAL and fibrotic markers.In addition,the level of serum PTEN was decreased in response to I/R,and was negatively correlated with serum creatinine.RPTC-specific PTEN overexpression relieved I/R-induced maladaptive repair,as indicated by alleviative tubular cell damage,apoptosis,and subsequent renal fibrosis.Mass spectrometry analysis revealed that differentially expressed proteins in RPTC-specific PTEN overexpression mice subjected to I/R were significantly enriched in phagosome,PI3K/Akt,and HIF-1 signaling pathway,and found significant upregulation of CHMP2A,an autophagy-related protein.PTEN deficiency downregulated CHMP2A,and inhibited phagosome closure and autolysosome formation,which aggravated cell injury and apoptosis after I/R.PTEN overexpression had the opposite effect.However,the beneficial effect of PTEN overexpression on autophagy flux and cell damage was abolished when CHMP2A was silenced.ConclusionsCollectively,PTEN was downregulated in kidney exposed to I/R-induced renal acute injury and maladaptive repair,and was associated with the severity of I/R.The serum PTEN concentration was a promising biomarker for assessing the severity of AKI and AKI to CKD transition.RPTC-specific PTEN overexpression alleviated acute renal injury and slowed down the progression of CKD.Innovatively,PTEN relieved renal injury and maladaptive repair in terms of cell damage,apoptosis,and renal fibrosis,by upregulating CHMP2A-mediated phagosome closure,suggesting PTEN/CHMP2A-mediated autophagy flux may serve as a novel therapeutic target for AKI and the AKI to CKD transition.