Low dose of sodium-glucose transporter 2 inhibitor ipragliflozin attenuated renal dysfunction and interstitial fibrosis in adenine-induced chronic kidney disease in mice without diabetes

BACKGROUND: Sodium–glucose co-transporter 2 (SGLT2) inhibitor, a new class of glucose lowering agents, has been shown to be reno-protective in diabetes. OBJECTIVE: We aimed to explore whether SGLT2 inhibitor ipragliflozin has a direct reno-protective effect on non-diabetic chronic kidney disease (CKD) in mice. METHODS: CKD mice was induced by feeding of 0.25% w/w adenine containing diet. Low dose ipragliflozin (0.03 or 0.1 mg/kg/day) was orally administered to CKD mice for 4 weeks, concomitantly with adenine containing diet. RESULTS: CKD mice exhibited increases in kidney weight/body weight ratio, plasma creatinine levels, urinary fatty acid binding protein 1 excretion and plasma interleukin-6 levels, and a decrease in hematocrit, accompanied by morphological changes such as crystal deposits in the tubules, tubular dilatation, interstitial fibrosis, and increased 8-hydroxy-2′-deoxyguanosine staining. Low dose ipragliflozin (0.03 or 0.1 mg/kg/day) did not affect either plasma glucose levels or urinary glucose excretion, while it improved levels in plasma creatinine (P < 0.05 for 0.03 mg/kg/day, P < 0.001 for 0.1 mg/kg/day), interleukin-6 (P < 0.05 for 0.1 mg/kg/day) and hematocrit (P < 0.05 for 0.1 mg/kg/day), and morphological changes dose-dependently except crystal deposit formation in the CKD mice. CONCLUSIONS: Low-dose ipragliflozin has a reno-protective effect in non-diabetic adenine-induced CKD mice, independently of plasma glucose levels and urinary glucose excretion. Low dose SGLT2 inhibitor may be a useful therapeutic option for non-diabetic CKD with the advantage of fewer adverse effects.