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논문분류	춘계학술대회 초록집
제목	Long-term administration of empagliflozin contributes to polyuria via transcriptional and post-translational control of aquaporin-2 in diabetic rat kidneys
저자	Sungjin Chung1, Soojeong Kim2, Minyoung Kim1, Seok Joon Shin1, Cheol Whee Park1, Yoon Sik Chang1, Ho-Shik Kim2, Eun Sil Koh1
출판정보	2018; 2018(1):
키워드	Sodium-glucose cotransporter-2 \| Empagliflozin \| Diuresis \| Sodium transport \| Water channel
초록	Objectives: A recent trial indicated that besides lowering glucose, empagliflozin, a selective sodium-glucose cotransporter-2 (SGLT2) inhibitor, may provide remarkable 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. Methods: This study was performed to assess the effects of a 12-week treatment with empagliflozin (3 mg/kg) on renal tubular function, related sodium transporters and water channels in diabetic OLETF rats by comparing it with other antihyperglycemic agents that included lixisenatide (10 μg/kg), a glucagon-like peptide receptor-1 agonist, and voglibose (0.6 mg/kg), an α-glucosidase inhibitor. Results: At 12 weeks of treatment, the serum sodium level and fractional excretion of sodium were not significantly different between empagliflozin-treated and control diabetic rats. Empagliflozin-treated diabetic rats produced slightly decreased, but still high, urine volume and glycosuria, and showed significantly higher electrolyte-free water clearance than lixisenatide-treated diabetic rats. In empagliflozin-treated rats, renal protein expression of Na+-K+-2Cl- cotransporter (NKCC2), Na+/H+ exchanger isoform 3 (NHE3) and γ-epithelial Na+ channel (ENaC) were decreased, and Na+-Cl- cotransporter (NCC) and α-ENaC expressions were unaltered compared with control diabetic rats. Empagliflozin increased the expressions of aquaporin (AQP)-1 and AQP7 but did not affect AQP3 protein expression in diabetic kidneys. Despite the increased expression in vasopressin V2 receptor (V2R), protein and mRNA levels of AQP2 in kidneys of empagliflozin-treated diabetic rats were significantly decreased compared to control diabetic rats. In addition, empagliflozin tended to increase the phosphorylation of AQP2 at S261 through the increased cyclin-dependent kinases 1 and 5 and protein phosphatase 2B. Conclusions: The collective results indicate that the longer use of empagliflozin may contribute in part to polyuria via transcriptional and post-translational regulation of AQP2 in diabetic rats.
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