WITHDRAWN: SGLT2i reduces renal injury by improving mitochondrial metabolism and biogenesis

Despite advances in treatment, an effective therapeutic strategy for acute kidney injury (AKI) is still lacking. Considering the widely reported clinical benefits of canagliflozin in the kidneys, we assessed the effects of canagliflozin on AKI. Lipopolysaccharide was used to induce AKI in the presence of canagliflozin. Canagliflozin treatment reduced blood urea nitrogen and serum creatinine levels and improved the renal tubular structure in mice with lipopolysaccharide-induced septic AKI. Canagliflozin also suppressed the inflammatory response, oxidative stress and tubular cell death in the kidneys during septic AKI. In vitro, canagliflozin supplementation maintained mitochondrial function in lipopolysaccharide-treated HK-2 cells by restoring the mitochondrial membrane potential, inhibiting mitochondrial reactive oxygen species production and normalizing mitochondrial respiratory complex activity. In HK-2 cells, canagliflozin stimulated the adenosine monophosphate-activated protein kinase catalytic subunit alpha 1 (AMPKα1)/peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α)/nuclear respiratory factor 1 (NRF1) pathway, thus elevating the number of live and healthy mitochondria following lipopolysaccharide treatment. Inhibition of the AMPKα1/PGC1α/NRF1/mitochondrial biogenesis pathway abolished the protective effects of canagliflozin on renal cell mitochondria and tubular viability. Similarly, the protective effects of canagliflozin on kidney function and tubular structure were abrogated in AMPKα1-knockout mice. Canagliflozin could be used to treat septic AKI by activating the AMPKα1/PGC1α/NRF1/mitochondrial biogenesis pathway.