Abstract
Sodium-glucose cotransporter 2 inhibitors, which are recently introduced as glucose-lowering agents, improve cardiovascular and renal outcomes in patients with diabetes mellitus. These drugs also have beneficial effects in various kidney disease models. However, the effect of SGLT2 inhibitors on cisplatin-induced acute kidney injury (AKI) and their mechanism of action need to be elucidated. In this study, we investigated whether canagliflozin protects against cisplatin-induced AKI, depending on adenosine monophosphate-activated protein kinase (AMPK) activation and following induction of autophagy. In the experiments using the HK-2 cell line, cell viability assay and molecular analysis revealed that canagliflozin protected renal proximal tubular cells from cisplatin, whereas addition of chloroquine or compound C abolished the protective effect of canagliflozin. In the mouse model of cisplatin-induced AKI, canagliflozin protected mice from cisplatin-induced AKI. However, treatment with chloroquine or compound C in addition to administration of cisplatin and canagliflozin eliminated the protective effect of canagliflozin. Collectively, these findings indicate that canagliflozin protects against cisplatin-induced AKI by activating AMPK and autophagy in renal proximal tubular cells.
Highlights
Sodium-glucose cotransporter 2 (SGLT2) inhibitors showed glucose-lowering effects and showed unexpected cardioprotective and renoprotective effects in patients with type 2 diabetes mellitus in large clinical trials [1,2,3,4,5,6]
Canagliflozin protects HK-2 cells from cisplatin by inhibiting apoptosis To test whether canagliflozin protects HK-2 cells from cisplatininduced cytotoxicity, HK-2 cells were treated with 20 μM cisplatin and 1–25 μM canagliflozin for 24 h because treatment with 20 μM cisplatin for 24 h showed 50% cell viability compared to the control and a pharmacokinetics study revealed that the daily approved dose of canagliflozin shows a peak plasma concentration of 10 μM in humans and concentrations of canagliflozin did not affect cell viability compared to the control (Supplementary Fig. 1A–C) [26]
Cisplatin-only treated cells showed 50% cell viability compared to the control, and cells treated with cisplatin + 25 μM canagliflozin showed 80% cell viability compared to the control
Summary
Sodium-glucose cotransporter 2 (SGLT2) inhibitors showed glucose-lowering effects and showed unexpected cardioprotective and renoprotective effects in patients with type 2 diabetes mellitus in large clinical trials [1,2,3,4,5,6]. The evidence that the renoprotective effect of SGLT2 inhibitors occurs regardless of the glucoselowering properties supports the rationale for testing the therapeutic use of the drugs to treat other kidney diseases. Cisplatin-induced AKI has been one of the most frequently used mouse models for tubulotoxic AKI with its simplicity, reproducibility, and clinical relevance [15]. Many studies using the mouse model of cisplatin-induced AKI to test therapeutic measures for tubulotoxic AKI have been conducted, the effects of renoprotective strategies derived from those studies are mostly partial or limited [14]
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