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- Publisher Website: 10.1038/s41419-022-05395-3
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Article: Tubular β-catenin alleviates mitochondrial dysfunction and cell death in acute kidney injury
Title | Tubular β-catenin alleviates mitochondrial dysfunction and cell death in acute kidney injury |
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Authors | |
Issue Date | 20-Dec-2022 |
Publisher | Springer Nature [academic journals on nature.com] |
Citation | Cell Death and Disease, 2022, v. 13, n. 12 How to Cite? |
Abstract | 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. |
Persistent Identifier | http://hdl.handle.net/10722/338822 |
ISSN | 2021 Impact Factor: 9.685 2020 SCImago Journal Rankings: 2.482 |
DC Field | Value | Language |
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dc.contributor.author | Li, Hongyu | - |
dc.contributor.author | Leung, Joseph C K | - |
dc.contributor.author | Yiu, Wai Han | - |
dc.contributor.author | Chan, Loretta Y Y | - |
dc.contributor.author | Li, Bin | - |
dc.contributor.author | Lok, Sarah W Y | - |
dc.contributor.author | Xue, Rui | - |
dc.contributor.author | Zou, Yixin | - |
dc.contributor.author | Lai, Kar Neng | - |
dc.contributor.author | Tang, Sydney C W | - |
dc.date.accessioned | 2024-03-11T10:31:49Z | - |
dc.date.available | 2024-03-11T10:31:49Z | - |
dc.date.issued | 2022-12-20 | - |
dc.identifier.citation | Cell Death and Disease, 2022, v. 13, n. 12 | - |
dc.identifier.issn | 2041-4889 | - |
dc.identifier.uri | http://hdl.handle.net/10722/338822 | - |
dc.description.abstract | <p>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.</p> | - |
dc.language | eng | - |
dc.publisher | Springer Nature [academic journals on nature.com] | - |
dc.relation.ispartof | Cell Death and Disease | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.title | Tubular β-catenin alleviates mitochondrial dysfunction and cell death in acute kidney injury | - |
dc.type | Article | - |
dc.identifier.doi | 10.1038/s41419-022-05395-3 | - |
dc.identifier.scopus | eid_2-s2.0-85144261589 | - |
dc.identifier.volume | 13 | - |
dc.identifier.issue | 12 | - |
dc.identifier.eissn | 2041-4889 | - |
dc.identifier.issnl | 2041-4889 | - |