Effect of Dapagliflozin Treatment on Fluid and Electrolyte Balance in Diabetic Rats

• Type of Material: Article
• Authors: Ling Chen, Emory University; Lauren LaRocque LaRocque, Emory University; Orhan Efe, Emory University; Juan Wang, Emory University; Jeff Sands, Emory University; Janet Klein, Emory University
• Language: English
• Date: 2016-11
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.amjms.2016.08.015
• Title of Journal or Parent Work: The American Journal of the Medical Sciences
• ISSN: 0002-9629
• Volume: 352
• Issue: 5
• Start Page: 517
• End Page: 523
• Grant/Funding Information: This work was supported by NIH grants DK41707 and DK89828
• Keywords: Diabetes mellitus; NITRIC-OXIDE; Life Sciences & Biomedicine; CISPLATIN-INDUCED POLYURIA; UREA TRANSPORTER; URINE CONCENTRATION; General & Internal Medicine; SGLT2 INHIBITOR; Medicine, General & Internal; NEPHROPATHY; EXPRESSION; Science & Technology; Urine concentration; SODIUM; Sodium glucose cotransporter 2; Kidney; TUBULAR CELLS; GLUCOSE-TRANSPORT
• Research Categories: Biology, Physiology

Abstract

AIM: This study evaluates the effect of dapagliflozin, a SGLT2 inhibitor, on fluid or electrolyte balance and its effect on urea transporter-A1 (UT-A1), aquaporin-2 (AQP2) and Na-K-2Cl cotransporter (NKCC2) protein abundance in diabetic rats. METHODS: Diabetes mellitus (DM) was induced by injection of streptozotocin into the tail vein. Serum Na+, K+, Cl- concentration, urine Na+, K+, Cl- excretion, blood glucose, urine glucose excretion, urine volume, urine osmolality and urine urea excretion were analyzed after the administration of dapagliflozin. UT-A1, AQP2 and NKCC2 proteins were detected by western blot. RESULTS: Dapagliflozin treatment decreased blood glucose concentration by 38% at day 7 and by 47% at day 14 and increased the urinary glucose excretion rate compared with the untreated diabetic animals. Increased 24-hour urine volume, decreased urine osmolality and hyponatremia, hypokalemia and hypochloremia observed in diabetic rats were attenuated by dapagliflozin treatment. Western blot analysis showed that UT-A1, AQP2 and NKCC2 proteins are upregulated in DM rats over control rats; dapagliflozin treatment results in a further increase in inner medulla tip UT-A1 protein abundance by 42% at day 7 and by 46% at day 14, but it did not affect the DM-induced upregulation of AQP2 and NKCC2 proteins. CONCLUSION: Dapagliflozin treatment augmented the compensatory changes in medullary transport proteins in DM. These changes would tend to conserve solute and water even with persistent glycosuria. Therefore, diabetic rats treated with dapagliflozin have a mild osmotic diuresis compared to nondiabetic animals, but this does not result in an electrolyte disorder or significant volume depletion.