Tubular β-Catenin Ameliorates AKI by Restoring Mitochondrial Biogenesis

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Background: Renal tubular β-catenin signaling plays a protective role in acute kidney injury (AKI), but the underlying mechanisms remain unclear. Mitochondrial dysfunction is responsible for the pathogenesis of AKI. This study aims to investigate the role of β-catenin activation on mitochondrial biogenesis in tubular cells upon AKI and its underlying mechanism. Methods: Loss- and gain-of-β-catenin function was established in mice with tubular cell-specific β-catenin stabilization (TubCat mice) and knockout (TubCatKO mice). Septic and aseptic AKI was induced by exposure to LPS or ischemia/reperfusion, respectively. Kidney injury was examined by NGAL immunohistochemical staining. Markers of mitochondrial biogenesis were determined by Western blot, real-time quantitative PCR and immunofluorescence staining. Signaling cascade was examined by Western blot. Results: Compared to the controls, TubCat mice under septic and aseptic AKI had significantly alleviated kidney injury and enhanced mitochondrial biogenesis as indicated by (i) reduction of NGAL positive tubules; (ii) restoration of mitochondrial mass protein TOMM20 and mitochondrial biogenesis molecules PGC-1α and NRF1; (iii) increasing co-localization of PGC-1α and β-catenin in renal tubules and (iv) increasing FOXO3 signaling against septic and aseptic injury. Consistently, kidney injury, and mitochondrial dysfunction were aggravated in TubCatKO mice versus their control littermates. Conclusions: In both septic and aseptic AKI, tubular β-catenin stabilization restores mitochondrial homeostasis through the FOXO3/PGC-1α signaling pathway. Funding: General Research Fund (HKU 17119818), RGC Collaborative Research Fund (Ref: C7018-16G) and Hong Kong Society of Nephrology Research Grant (2019)

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