Tubular β-Catenin Ameliorates AKI by Regulating Apoptosis and Necroptosis

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Background: Renal tubular β-catenin signaling plays a protective role in acute kidney injury (AKI) but the underlying mechanisms remain debatable. Apoptosis and necroptosis of tubular cells are responsible for the renal dysfunction in AKI. This study aims to investigate the role of β-catenin activation in tubular cell death upon AKI and its underlying mechanism. Methods: Transgenic ‘Tubcat’ mice conditionally expressing stabilized β-catenin in renal tubules following tamoxifen administration were used to establish septic (LPS-induced) and non-septic (ischemia-reperfusion injury or IRI-induced) AKI models. Tubcat mice and their littermate controls were divided into the LPS and IRI groups. LPS mice received intraperitoneal injection of LPS (20 mg/kg). IRI mice received bilateral ischemia for 28 minutes, followed by 24 hours of reperfusion. All the mice were sacrificed at 24 hours. Kidney function and renal histological changes were assessed. Renal apoptosis and necroptosis were evaluated by real-time quantitative PCR, western blot and TUNEL assay. Signaling cascade was examined by western blot. Results: Compared to the controls, Tubcat mice under septic and non-septic AKI had significantly improved renal function (lower serum creatinine levels) and reduction of (i) tubular injury score; (ii) apoptosis (Bax/Bcl2 ratio and number of renal TUNEL-positive apoptotic cells); (iii) necroptosis (expression of RIP1, p-RIP3 and p-MLKL); and (iv) renal expression of phosphorylated p53. Renal expression of phosphorylated Akt was increased significantly. Conclusions: Activation of β-catenin signaling in tubular cells reduces apoptosis and necroptosis in septic and non-septic AKI. Tubular β-catenin might play a protective role in AKI by regulating cell death via modulating the p53/Akt signaling pathway. Fundings: General Research Fund (HKU 17119818), RGC Collaborative Research Fund (Ref: C7018-16G) and Hong Kong Society of Nephrology Research Grant (2019) Funding: Government Support - Non-U.S.

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