Tubular β-catenin alleviates mitochondrial dysfunction and cell death in acute kidney injury.
Hong-Yu LiJoseph C K LeungWai Han YiuLoretta Y Y ChanBin LiSarah W Y LokRui XueYixin ZouKar Neng LaiSydney Chi-Wai TangPublished in: Cell death & disease (2022)
Mitochondria take part in a network of intracellular processes that regulate homeostasis. Defects in mitochondrial function are key pathophysiological changes during AKI. Although Wnt/β-catenin signaling mediates mitochondrial dysfunction in chronic kidney fibrosis, little is known of the influence of β-catenin on mitochondrial function in AKI. To decipher this interaction, we generated an inducible mouse model of tubule-specific β-catenin overexpression (TubCat), and a model of tubule-specific β-catenin depletion (TubcatKO), and induced septic AKI in these mice with lipopolysaccharide (LPS) and aseptic AKI with bilateral ischemia-reperfusion. In both AKI models, tubular β-catenin stabilization in TubCat animals significantly reduced BUN/serum creatinine, tubular damage (NGAL-positive tubules), apoptosis (TUNEL-positive cells) and necroptosis (phosphorylation of MLKL and RIP3) through activating AKT phosphorylation and p53 suppression; enhanced mitochondrial biogenesis (increased PGC-1α and NRF1) and restored mitochondrial mass (increased TIM23) to re-establish mitochondrial homeostasis (increased fusion markers OPA1, MFN2, and decreased fission protein DRP1) through the FOXO3/PGC-1α signaling cascade. Conversely, kidney function loss and histological damage, tubular cell death, and mitochondrial dysfunction were all aggravated in TubCatKO mice. Mechanistically, β-catenin transfection maintained mitochondrial mass and activated PGC-1α via FOXO3 in LPS-exposed HK-2 cells. Collectively, these findings provide evidence that tubular β-catenin mitigates cell death and restores mitochondrial homeostasis in AKI through the common mechanisms associated with activation of AKT/p53 and FOXO3/PGC-1α signaling pathways.
Keyphrases
- acute kidney injury
- cell cycle arrest
- cell proliferation
- cell death
- pi k akt
- oxidative stress
- signaling pathway
- epithelial mesenchymal transition
- induced apoptosis
- high glucose
- cardiac surgery
- skeletal muscle
- mouse model
- transcription factor
- diabetic rats
- inflammatory response
- endothelial cells
- stem cells
- protein kinase
- metabolic syndrome
- small molecule
- radiation therapy
- adipose tissue
- protein protein
- amino acid