Dapagliflozin Does Not Protect against Adriamycin-Induced Kidney Injury in Mice

Abstract

Introduction: Sodium–glucose cotransporter 2 (SGLT2) inhibitors target SGLT2 in renal proximal tubules and promote glycosuria in type 2 diabetes mellitus in humans and animal models, resulting in reduced blood glucose levels. Although clinical trials have shown that SGLT2 inhibitors attenuate the progression of chronic kidney disease, there have been concerns regarding SGLT2-induced acute kidney injury. In this study, we investigated the effect of SGLT2 inhibitors on adriamycin-induced kidney injury in mice. Methods: Seven-week-old balb/c mice were injected with adriamycin 11.5 mg/kg via the tail vein. Additionally, dapagliflozin was administered via gavage for 2 weeks. The mice were divided into five groups: vehicle, dapagliflozin 3 mg/kg, adriamycin, adriamycin plus dapagliflozin 1 mg/kg, and adriamycin plus dapagliflozin 3 mg/kg. Results: Adriamycin injection reduced the body weight and food and water intakes. Dapagliflozin also decreased the body weight and food and water intakes. Fasting blood glucose and urine volume were not altered by either adriamycin or dapagliflozin. Once adriamycin-induced kidney injury had developed, there were no differences in systolic blood pressure among the groups. Dapagliflozin did not alleviate proteinuria in adriamycin-induced kidney injury. Adriamycin induced significant glomerular and interstitial injury, but dapagliflozin did not attenuate these changes in renal injury. Interstingly, SGLT2 expressions were different between the cortex and medulla of kidneys by dapagliflozin treatment. Dapagliflozin increased SGLT2 expression in medulla, not in cortex. Conclusion: Dapagliflozin had no effect on proteinuria or inflammatory changes such as glomerular and tubular damages in adriamycin-induced kidney injury. Our study suggests that dapagliflozin does not protect against adriamycin-induced kidney injury. More experimental studies regarding the effects of SGLT2 inhibitors on various kidney diseases are needed to clarify the underlying mechanisms.

Sodium Glucose Cotransporter-2 Inhibitors in Non-Diabetic Kidney Disease: Evidence in Experimental Models

“…In fact, in some cases, SGLT2 inhibitors show beneficial effects by protecting the kidneys and improving functional parameters (plasma creatinine and urea, glomerular filtration rate, urinary protein excretion) and tissue parameters (kidney weight, glomerular and tubular structural dysfunctions, interstitial fibrosis, inflammatory cellular infiltration and oxidative stress) [ 20 , 21 , 23 , 25 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 35 , 36 , 37 , 38 , 39 , 41 , 44 , 45 , 47 , 49 , 50 , 51 , 52 ]. In other cases, however, SGLT2 inhibitors seem to have no protective impact on the kidney [ 22 , 24 , 26 , 34 , 35 , 40 , 42 , 43 , 46 , 48 ]. Altogether, it seems reasonable to assume that the administration of SGLT2 inhibitors may have different effects in animal models of different diseases in different animal strains; and, in any case, the effect of these drugs could be influenced by the duration of the disease and by the duration of the treatment.…”

“…In balb/c mice, adriamycin administration caused proteinuria and kidney injury, which were not modified by SGLT2 inhibition. In fact, dapagliflozin administration (1 or 3 mg/kg/day for 2 weeks) did not ameliorate proteinuria, glomerulosclerosis, tubulointerstitial inflammation, fibrosis, tubular casts and tubular atrophy, suggesting that SGLT2 inhibition has no nephroprotective effects in adriamycin-induced kidney injury ( Table 2 ) [ 40 ].…”