Abstract
Phosphatase and Tensin Homolog on chromosome Ten (PTEN) has emerged as a key protein that governs the response to kidney injury. Notably, renal adaptive repair is important for preventing acute kidney injury (AKI) to chronic kidney disease (CKD) transition. To test the role of PTEN in renal repair after acute injury, we constructed a mouse model that overexpresses PTEN in renal proximal tubular cells (RPTC) by crossing PTENfl-stop-fl mice with Ggt1-Cre mice. Mass spectrometry-based proteomics was performed after subjecting these mice to ischemia/reperfusion (I/R). We found that PTEN was downregulated in renal tubular cells in mice and cultured HK-2 cells subjected to renal maladaptive repair induced by I/R. Renal expression of PTEN negatively correlated with NGAL and fibrotic markers. 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. Notably, the beneficial effect of PTEN overexpression on autophagy flux and cell damage was abolished when CHMP2A was silenced. Collectively, our study suggests that PTEN relieved renal maladaptive repair in terms of cell damage, apoptosis, and renal fibrosis by upregulating CHMP2A-mediated phagosome closure, suggesting that PTEN/CHMP2A may serve as a novel therapeutic target for the AKI to CKD transition.
Highlights
Acute kidney injury (AKI) is a syndrome defined by rapid loss of renal function and occurs in ~10–15% of in-hospital patients, and >50% of patients admitted to the intensive care unit [1, 2]
Using mass spectrometry (MS)-based In HK-2 cells, when Phosphatase and Tensin Homolog on chromosome Ten (PTEN) expression was reduced by antimycin proteomics, we found that CHMP2A was significantly increased in A-mediated I/R stimulation, NGAL expression increased and cell
Immunoblotting and response to hypoxia in I/R condition immunohistochemical analyses revealed that, at 25 and 35 min A heat map based on our MS data showed distinct patterns of obstruction, I/R caused a significant decrease in PTEN expression and an increased neutrophil gelatinaseprotein expression in the kidney when comparing sham, BIRI, and BIRI + PTEN-OE (PTEN-OE was abbreviated for PTENfl-stop-fl, Cre+/+)
Summary
Acute kidney injury (AKI) is a syndrome defined by rapid loss of renal function and occurs in ~10–15% of in-hospital patients, and >50% of patients admitted to the intensive care unit [1, 2]. Aside from its high mortality, AKI can trigger immediate kidney damage (referred to as acute kidney disease) or long-term damage (in the form of chronic kidney disease (CKD) and end-stage renal disease), both due to maladaptive repair [3,4,5]. The relationship between AKI and CKD is determined by the severity of renal tubule damage; and if renal tubule damage is alleviated in the acute-injury stage and adaptive repair is facilitated, tubular structure and function can be restored to normalcy. AKI experimental models detected altered autophagy an intracellular degradation process that is essential for physiological function and survival of renal tubular cells [8,9,10]. Whether and how autophagy flux works in the pathogenesis of renal I/R injury and repair remains controversial
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