Abstract: TH-PO0028
Multilevel Inhibition of Urate Transporters and Insulin-Activated Urate Transport by SGLT2 Inhibitors
Session Information
- Fluid, Electrolyte, and Acid-Base Disorders: Basic Research
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Fluid, Electrolytes, and Acid-Base Disorders
- 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic
Authors
- Mount, David B., Mass General Brigham Inc, Boston, Massachusetts, United States
- Mandal, Asim, Mass General Brigham Inc, 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 mechanism(s) of these uricosuric effects is 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 and SGLT1/2.
Results
SGLT2i significantly inhibited net urate uptake in a dose-dependent manner in human PTC-05 cells, which express endogenous multiple glucose transporters, including SGLT1/2, and multiple urate transporters. In the Xenopus laevis oocyte expression system, SGLT2i significantly inhibited the basal urate transport activities of URAT1, OAT10, OAT3 and ABCC4 but not GLUT9; SGLT2is did however reduce protein expression of GLUT9 in PTC-05 cells. For URAT1, the IC50s for empagliflozin, canagliflozin, and dapagliflozin were 460, 230, and 487 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. In oocytes, SGLT2i inhibited insulin-activated GLUT9a urate transporter and abrogated activation of Akt/ERK, but surprisingly in oocytes expressing SGLT1, not SGLT2. SGLT2i also activated AMPK in PTC-5 cells and in oocytes expressing SGLT1.
Conclusion
The results indicate that the uricosuric action of SGLT2 inhibitors is at least partially the consequence of impairment of the basal activities of the apical urate reabsorptive transporters URAT1 and OAT10. Additionally, SGLT2 inhibitors inhibit insulin-activated transport in proximal tubular cells and oocytes co-expressing SGLT1 with GLUT9a, with attenuated phosphorylation of Akt and ERK. SGLT2i also influences AMPK activation in both systems, indicating complex effects on insulin/urate-related cell signaling.
Funding
- Other NIH Support