Validation of Nephrotoxicity Suppression by SGLT-2 Inhibitors Using the Kidney-on-a-Chip Model

초록

Sodium-glucose cotransporter (SGLT)-2 inhibitors are used for the treatment of diabetes mellitus owing to their hypoglycemic effects and for cardiovascular disease prevention and renoprotection. They are used as the main therapeutic agents to preserve the renal function in patients with chronic kidney disease, including patients without diabetes. Several studies have reported the beneficial effects of SGLT-2 inhibitors against drug-induced acute nephrotoxicity. In this study, we aimed to investigate the inhibitory effects of the SGLT-2 inhibitors, canagliflozin, and empagliflozin, on nephrotoxicity using a kidney-on-a-chip model, instead of animal models, to culture human renal proximal tubule epithelial cells. Cell viability, transepithelial electrical resistance, glucose reabsorption, and nephrotoxicity were compared between samples first treated with canagliflozin or empagliflozin and then with cisplatin and those treated with cisplatin alone. Permeability, immunofluorescence, and enzyme-linked immunosorbent assays were also performed. Canagliflozin and empagliflozin inhibited the nephrotoxicity in samples. The effects of drug administration direction and type on nephrotoxicity inhibition were also determined. For both drugs, the apical side (human renal proximal tubule epithelial cells) was more effective than the basolateral side (human umbilical vein endothelial cells). Moreover, canagliflozin was more effective than empagliflozin in inhibiting nephrotoxicity. In conclusion, these results suggest the potential of the kidney-on-a-chip technology for drug development as an alternative to animal models, whose application is associated with heterogeneous differences and ethical issues.

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