Canagliflozin Promotes Mitochondrial Biogenesis in Glycerol-Induced Acute Kidney Injury by Activating the AMPK/SIRT1/FOXO-3a/ PGC-1α and Nrf2/HO-1 Trajectories

Abstract

Background: A sodium-glucose-linked co-transporter-2 (SGLT-2) inhibitor, canagliflozin (Cana), reportedly exhibits protective effects against several models of kidney injury. However, its possible involvement in preventing glycerol (Gly)-induced acute kidney injury (AKI) is currently unknown.

Aim: Thus, the purpose of this work is to demonstrate for the first time the protective role of Cana through adenosine-monophosphate-activated protein kinase (AMPK)/sirtuin-1 (SIRT1)/forkhead box O-3 (FOXO-3a)/peroxisome proliferator-activated receptor-gamma co-activator-1 alpha (PGC-1α) pathway against Gly-induced AKI in rats.

Main methods: Rats were randomly allocated into five groups: normal, Gly, Gly pretreated with 10 mg/kg Cana, and Gly pretreated with Cana 25 mg/kg, and normal pretreated with Cana 25 mg/kg for 14 constitutive days.

Key findings: Pretreatment with Cana ameliorated kidney functions manifested by reducing serum creatinine, BUN, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule (Κim-1). Moreover, Cana also opposed the Gly-induced elevation in tissue contents of nuclear factor-κB (NF-кB) and interleuκin-6 (IL-6) and reserved the antioxidant pool through increasing superoxide dismutase (SOD), Manganese SOD (MnSOD), and heme oxygenase-1 (HO-1) activities. Nevertheless, Cana increased the protein expressions of the AMPK/SIRT1/FOXO-3a/PGC-1α axis besides the transcriptional activity of growth arrest and DNA damage-inducible protein alpha (GAAD45a). Additionally, the elevation of nuclear factor erythroid 2-related factor 2 (Nrf2) was noted in rats treated with Cana detected by immunohistochemistry. Finally, Cana significantly ameliorated Gly-induced histopathological changes.

Significance: In conclusion, Cana purveyed potentially novel renoprotective mechanisms and eased incidents associated with AKI through the elevation of AMPK/SIRT1/FOXO-3a/PGC-1α in addition to Nrf2/HO-1 apart from the amendment of the biomarkers mentioned above.

Note:
Funding Information: This study was not supported by any particular grant from the public, commercial, or not-for-profit funding bodies

Declaration of Interests: The authors have disclosed no conflicts of interest.

Ethical Approval Statement: The National Institutes of Health's Guide for the Care and Use of Laboratory Animals was followed while caring for the male Wistar rats (NIH publication No. 85-23, updated 2011), permitted by the Faculty of Pharmacy's Research Ethics Committee (permission number: PO 121).

Keywords: Acute kidney injury, Canagliflozin, glycerol, PGC-1α, AMPK/SIRT1/FOXO-3a, Nrf2/HO-1