Canagliflozin potentially promotes renal protection against glycerol-induced acute kidney injury by activating the AMPK/SIRT1/FOXO-3a/PGC-1α and Nrf2/HO-1 pathways

The reno-protective potential of canagliflozin (Cana), an inhibitor of the sodium glucose-linked co-transporter-2 (SGLT-2), has been demonstrated in different models of kidney injury. However, its potential role in preventing glycerol (Gly)-induced acute kidney injury (AKI) remains to be divulged. Therefore, the aim of this study is to investigate the potential reno-protective effect of Cana and its underlying mechanism in a rat model of Gly-induced AKI. Rats were randomly allocated into five groups: normal, Gly, Gly pretreated with 10 mg/kg Cana, Gly pretreated with Cana 25 mg/kg, and normal pretreated with Cana 25 mg/kg for 14 consecutive days. Pretreatment with Cana improved renal structure and enhanced kidney functions manifested by reducing serum creatinine and blood urea nitrogen, as well as renal contents of neutrophil gelatinase-associated lipocalin and kidney injury molecule. Moreover, Cana signified its anti-inflammatory effect by reducing the Gly-induced elevation in renal contents of nuclear factor-κB and interleuκin-6. Additionally, Cana augmented the defense enzymatic antioxidants superoxide dismutase (SOD), manganese-SOD, and heme oxygenase-1, besides increasing the protein expression of the antioxidant transcription factor nuclear factor erythroid 2-related factor 2 to point for its ability to correct redox balance. Cana also upregulated the protein expression of the 5' adenosine monophosphate-activated protein kinase (AMPK), Sirtuin1 (SIRT1), Forkhead box protein O3 (FOXO-3a), and peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α), as well as the transcriptional activity of growth arrest and DNA damage-inducible protein alpha (GAAD45a). In conclusion, Cana demonstrated potentially novel reno-protective mechanisms and mitigated the consequences of AKI through its antioxidant and anti-inflammatory properties, partially by activating the AMPK/SIRT1/FOXO-3a/PGC-1α pathway.