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Abstract: FR-PO140

Aldehyde Dehydrogenase 2 Alleviates Mitochondrial Dysfunction by Regulating Aerobic Glycolysis via PI3K/AKT/mTOR Pathway in AKI

Session Information

  • AKI: Mechanisms - II
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Li, Jiaying, Peking Union Medical College Hospital, Dongcheng-qu, Beijing, China
  • Shi, Xiaoxiao, Peking Union Medical College Hospital, Dongcheng-qu, Beijing, China
  • Chen, Limeng, Peking Union Medical College Hospital, Dongcheng-qu, Beijing, China
Background

The protective roles of mitochondrial enzyme acetaldehyde dehydrogenase 2 (ALDH2) in various diseases have been reported. In this study, we aimed to investigate the role of ALDH2 on AKI with aerobic glycolysis via the PI3K/AKT/mTOR pathway in different AKI models.

Methods

AKI models were established by cisplatin (cis) or maleic acid (MA) intraperitoneally (i.p.) in wild type (WT) and ALDH2 knockout (KO) mice and Alda-1 (ALDH2 agonist) was administrated for prevention experiments. We observed mitochondrial function, aerobic glycolysis, and the PI3K/AKT/mTOR pathway in vivo and in vitro with human renal proximal tubular epithelial (HK-2) cells stimulated by activation or knockdown ALDH2. Furthermore, the rescue experiment was done by LY294002 (inhibitor of PI3K) in HK-2 cells transfected with ALDH2 shRNA (shALDH2) plasmid.

Results

ALDH2 protein was reduced by 46% and 28% in cisplatin and MA induced AKI mice, accompanied by proximal tubular injury and mitochondrial dysfunction. ALDH2 agonist Alda-1 prevented the increase of serum creatinine (Scr) (38.54±4.92 versus 74.42±4.39 μmol/L, P<0.0001) in WT cis-AKI, while more severe (86.13±6.20 versus 62.29±3.19 μmol/L, P<0.01) in ALDH2 KO cis-AKI. In the MA-AKI mice, the renal function (Scr: 20.09±3.65 versus 64.55±12.64 μmol/L, P<0.001) was recovered by Alda-1 pretreatment with reduced KIM-1 protein. In addition, decreased mitochondrial-related proteins (PGC-1α and ATP5a1), mitochondrial DNA (mtDNA) and ATP content were observed in MA-AKI, but reversed by pretreatment with Alda-1. In HK-2 cells, knockdown of ALDH2 aggravated MA-induced mitochondrial dysfunction, indicated by decreased mitochondrial membrane potential and mitochondrial oxygen consumption rate (OCR) (54.80 ± 7.34 versus 40.06 ± 3.58 pmol/min/ug.pro, P<0.05) with the activation of aerobic glycolysis and PI3K/AKT/mTOR pathway. Furthermore, LY294002 partially reversed the cell apoptosis percentage (15.50%± 0.67 versus 19.50% ± 0.68, P<0.05) of ALDH2 knockdown in MA-induced HK2 cells.

Conclusion

ALDH2 prevented tubular injury and apoptosis by rescuing mitochondrial dysfunction and aerobic glycolysis via the PI3K/AKT/mTOR pathway in cisplatin and MA-induced AKI.