PTEN Protects Against Ischemia/Reperfusion-Induced Acute Kidney Injury and Repair via Regulating CHMP2A-Mediated Autophagy Flux

Background: PTEN has been raised its role in kidney homeostasis. Previously, we demonstrated that podocyte-specific knock-in of PTEN alleviated albuminuria and glomerular sclerosis in mice with diabetic kidney disease. However, the role of PTEN in acute kidney injury (AKI) and repair remains unknown. Methods: Renal proximal tubular cells (RPTC)-specific PTEN overexpression mice were established by crossing PTENfl-stop-fl mice with Ggt1-Cre mice. Mass spectrometry (MS) of proteomics was performed among sham, BIRI, and BIRI+PTEN-OE mice .Findings PTEN was downregulated in serum and renal tubular cells ( RTC ) in mice subjected to I/R injury and repair. The concentration of serum PTEN was negatively correlated with serum creatinine. RPTC-specific PTEN overexpression alleviated I/R-induced renal injury and apoptosis, and subsequent renal fibrosis. MS analysis revealed that differentially expressed proteins (DEPs) between BIRI+PTEN-OE and BIRI mice were significantly enriched in phagosome, PI3K/AKT, and HIF-1 signaling and showed that CHMP2A was significantly changed among DEPs enriched in autophagy. Consistently, PTEN was downregulated in I/R-treated HK-2. PTEN deficiency accumulated autophagosome-bound LC3-II and P62 and inhibited autolysosome formation via downregulating CHMP2A, resulting in aggravated cell injury and apoptosis of HK-2 subjected to I/R, while overexpression of PTEN exhibited opposite effect. However, silencing CHMP2A abolished the effect of PTEN overexpression on autophagy flux and cell damage in I/R-treated HK-2. Interpretation: Our work implicates a critical role of PTEN in regulating CHMP2A-mediated phagosome closure in autophagy flux in RTC subjected to I/R-induced renal injury and repair, and provides evidence for PTEN/CHMP2A might serve as a novel target for I/R-AKI therapy. Funding: This work was supported by grants from the National Natural Science Foundation of China (No. 81770727), GDUPS (2017), Key Project of Guangzhou Science Technology and Innovation Commission (201804020054), the Natural Science Foundation of Guangdong (2021A1515011376), and Science and Technology Planning Project of Guangdong Province (2017A010103041). Declaration of Interest: None to declare. Ethical Approval: All animal experiments were approved by the Institutional Animal Care and Use Committee of Nanfang Hospital.