Abstract
Besides lowering glucose, empagliflozin, a selective sodium-glucose cotransporter-2 (SGLT2) inhibitor, have been known to provide cardiovascular and renal protection due to effects on diuresis and natriuresis. However, the natriuretic effect of SGLT2 inhibitors has been reported to be transient, and long-term data related to diuretic change are sparse. This study was performed to assess the renal effects of a 12-week treatment with empagliflozin (3 mg/kg) in diabetic OLETF rats by comparing it with other antihyperglycemic agents including lixisenatide (10 μg/kg), a glucagon-like peptide receptor-1 agonist, and voglibose (0.6 mg/kg), an α-glucosidase inhibitor. At 12 weeks of treatment, empagliflozin-treated diabetic rats produced still high urine volume and glycosuria, and showed significantly higher electrolyte-free water clearance than lixisenatide or voglibose-treated diabetic rats without significant change of serum sodium level and fractional excretion of sodium. In empagliflozin-treated rats, renal expression of Na+-Cl- cotransporter was unaltered, and expressions of Na+/H+ exchanger isoform 3, Na+-K+-2Cl- cotransporter, and epithelial Na+ channel were decreased compared with control diabetic rats. Empagliflozin increased an expression of aquaporin (AQP)7 but did not affect AQP3 and AQP1 protein expressions in diabetic kidneys. Despite the increased expression in vasopressin V2 receptor, protein and mRNA levels of AQP2 in empagliflozin-treated diabetic kidneys were significantly decreased compared to control diabetic kidneys. In addition, empagliflozin resulted in the increased phosphorylation of AQP2 at S261 through the increased cyclin-dependent kinases 1 and 5 and protein phosphatase 2B. These results suggest that empagliflozin may contribute in part to polyuria via its regulation of sodium channels and AQP2 in diabetic kidneys.
Highlights
MATERIALS AND METHODSA recent trial with empagliflozin, a selective sodium-glucose cotransporter type 2 (SGLT2) inhibitor, has shown the significant improvement in the primary major adverse cardiovascular event outcome, driven mainly by significant reductions in cardiovascular death and hospitalization for heart failure (Zinman et al, 2015; Heerspink et al, 2016; van Bommel et al, 2017)
The urine osmolality of all untreated and treated Otsuka Long-Evans Tokushima Fatty (OLETF) rats was significantly smaller than that of LETO rats, and no significant differences in urine osmolality were observed among the four diabetic rats (Figure 1B)
Diabetes mellitus in OLETF rats resulted in significant hyponatremia, whereas empagliflozin treatment of diabetic rats had no significant effect on serum Na level (Table 1)
Summary
MATERIALS AND METHODSA recent trial with empagliflozin, a selective sodium-glucose cotransporter type 2 (SGLT2) inhibitor, has shown the significant improvement in the primary major adverse cardiovascular event outcome, driven mainly by significant reductions in cardiovascular death and hospitalization for heart failure (Zinman et al, 2015; Heerspink et al, 2016; van Bommel et al, 2017). The dapagliflozin treatment during 7 and 14 days showed the significantly decreased urine volume and the increased urine osmolality, but there was no significant change in the expression of aquaporin (AQP) and Na+-K+-2Cl− cotransporter (NKCC2) proteins in the diabetic rat kidneys between dapagliflozin-treated and untreated diabetic rats (Chen et al, 2016). It is not clear how more prolonged use of a SGLT2 inhibitor would affect natriuresis and diuresis
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