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SGLT2 inhibition and renal urate excretion: the role of luminal glucose, GLUT9 and URAT1.
American Journal of Physiology. Renal Physiology 2018 November 15
Inhibitors of the sodium-glucose cotransporter SGLT2 enhance urinary glucose and urate excretion and lower plasma urate levels. The mechanisms remain unclear, but a role for enhanced glucose in the tubular fluid has been proposed, which may interact with tubular urate transporters like GLUT9 or URAT1. Studies were performed in non-diabetic mice using the SGLT2 inhibitor canagliflozin and gene targeted mice lacking the urate transporter GLUT9 in the tubule or mice with whole body knockout of SGLT2, SGLT1, or URAT1. Renal urate handling was assessed by analyzing urate in spontaneous plasma and urine samples and normalization to creatinine concentrations or renal clearance studies with assessment of GFR by FITC-sinistrin. The experiments confirmed the contribution of URAT1 and GLUT9 to renal urate reabsorption, showing a greater contribution of the latter and additive effects. Both genetic and pharmacologic inhibition of SGLT2 enhanced fractional renal urate excretion (FE-urate), indicating that a direct effect of the SGLT2 inhibitor on urate transporters is not absolutely necessary. Consistent with a proposed role of increased luminal glucose delivery, absence of SGLT1, which by itself had no effect on FE-urate, enhanced both the glycosuric and uricosuric effect of the SGLT2 inhibitor. The SGLT2 inhibitor enhanced renal mRNA expression of GLUT9 in WT mice, but tubular GLUT9 seemed dispensable for the increase in FE-urate in response to canagliflozin. First evidence is presented that URAT1 is required for the acute uricosuric effect of the SGLT2 inhibitor in mice.
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