Abstract: FR-OR29
Inhibition of Urate Transporters and Insulin-Activated Urate Transport by SGLT2 Inhibitors
Session Information
- Fluid, Electrolyte, and Acid-Base Disorders: Basic Research
November 03, 2023 | Location: Room 111, Pennsylvania Convention Center
Abstract Time: 05:42 PM - 05:51 PM
Category: Fluid, Electrolytes, and Acid-Base Disorders
- 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic
Authors
- Mount, David B., Brigham and Women's Hospital Department of Medicine, Boston, Massachusetts, United States
- Mandal, Asim, Brigham and Women's Hospital Department of Medicine, Boston, Massachusetts, United States
Background
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have well-established uricosuric and urate-lowering effects, with protective effects on gout. The mechanisms of these uricosuric effects are not clear, however, and direct effects on urate transporters have not been fully investigated. We report the effects of empagliflozin, canagliflozin, and dapagliflozin on urate transport in a human proximal tubular cell line and in Xenopus oocytes expressing individual urate transporters.
Methods
Western blotting, in vitro transcription of cRNA from cloned cDNA and urate transport assays in human renal proximal tubule epithelial cells (PTC-05) and Xenopus laevis oocytes expressing individual human urate transporters.
Results
SGLT2 inhibitors significantly inhibited net urate uptake in a dose-dependent manner in human PTC-05 cells, which express endogenous SGLT2 and the urate transporters GLUT9a, GLUT9b, OAT10, OAT1, NPT1, ABCG2 and ABCC4. In the Xenopus laevis oocyte expression system, these inhibitors inhibited the basal urate transport activities of URAT1, OAT10, OAT3 and ABCC4 but not GLUT9, OAT1, and ABCG2. OAT10 was only modestly sensitive to empagliflozin and canagliflozin (~38% and 28% inhibition with 500 µM empagliflozin and canagliflozin respectively). For URAT1, the IC50s for empagliflozin, canagliflozin, and dapagliflozin were 460, 230, and 487 µM, respectively; for OAT3 the IC50s were 42, 29, and 21 µM, respectively. In addition, SGLT2i inhibited insulin-induced stimulation of urate transport in PTC-05 cells, with dose-dependent inhibitory effects on insulin-induced phosphorylation of the downstream Akt and ERK kinases.
Conclusion
These results indicate that the uricosuric action of SGLT2 inhibitors is at least partially due to direct inhibition of the apical urate reabsorptive transporters URAT1 and OAT10. Additionally, SGLT2 inhibitors inhibited insulin-activated transport in a human proximal tubular cell line, with attenuated phosphorylation of Akt and ERK; given the key role for insulin-activated urate transport in the genesis of hyperuricemia this indicates another potential mechanism for SGLT2i-associated uricosuria.
Funding
- Other NIH Support