%0 Journal Article %1 novikov2019sglt2 %A Novikov, A. %A Fu, Y. %A Huang, W. %A Freeman, B. %A Patel, R. %A van Ginkel, C. %A Koepsell, H. %A Busslinger, M. %A Onishi, A. %A Nespoux, J. %A Vallon, V. %D 2019 %J Am J Physiol Renal Physiol %K Animals myOwn %N 1 %P F173-F185 %R 10.1152/ajprenal.00462.2018 %T SGLT2 inhibition and renal urate excretion: role of luminal glucose, GLUT9, and URAT1 %U https://www.ncbi.nlm.nih.gov/pubmed/30427222 %V 316 %X Inhibitors of the Na(+)-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, which may interact with tubular urate transporters, such as the glucose transporter GLUT9 or the urate transporter URAT1, has been proposed. Studies were performed in nondiabetic mice treated with the SGLT2 inhibitor canagliflozin and in gene-targeted mice lacking the urate transporter Glut9 in the tubule or in mice with whole body knockout of Sglt2, Sglt1, or Urat1. Renal urate handling was assessed by analysis of urate in spontaneous plasma and urine samples and normalization to creatinine concentrations or by renal clearance studies with assessment of glomerular filtration rate 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. Genetic and pharmacological 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, the absence of Sglt1, which by itself had no effect on FE-urate, enhanced the glycosuric and uricosuric effects of the SGLT2 inhibitor. The SGLT2 inhibitor enhanced renal mRNA expression of Glut9 in wild-type 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.

@article{novikov2019sglt2, abstract = {Inhibitors of the Na(+)-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, which may interact with tubular urate transporters, such as the glucose transporter GLUT9 or the urate transporter URAT1, has been proposed. Studies were performed in nondiabetic mice treated with the SGLT2 inhibitor canagliflozin and in gene-targeted mice lacking the urate transporter Glut9 in the tubule or in mice with whole body knockout of Sglt2, Sglt1, or Urat1. Renal urate handling was assessed by analysis of urate in spontaneous plasma and urine samples and normalization to creatinine concentrations or by renal clearance studies with assessment of glomerular filtration rate 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. Genetic and pharmacological 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, the absence of Sglt1, which by itself had no effect on FE-urate, enhanced the glycosuric and uricosuric effects of the SGLT2 inhibitor. The SGLT2 inhibitor enhanced renal mRNA expression of Glut9 in wild-type 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.}, added-at = {2024-02-15T15:08:22.000+0100}, author = {Novikov, A. and Fu, Y. and Huang, W. and Freeman, B. and Patel, R. and van Ginkel, C. and Koepsell, H. and Busslinger, M. and Onishi, A. and Nespoux, J. and Vallon, V.}, biburl = {https://www.bibsonomy.org/bibtex/2a088e65c6188a83813bdb269e2cf96a8/jvsi_all}, doi = {10.1152/ajprenal.00462.2018}, interhash = {8154d80754f7b7c18ec6b66848b91c20}, intrahash = {a088e65c6188a83813bdb269e2cf96a8}, issn = {1522-1466 (Electronic) 1931-857X (Print) 1522-1466 (Linking)}, journal = {Am J Physiol Renal Physiol}, keywords = {Animals myOwn}, note = {Novikov, Aleksandra Fu, Yiling Huang, Winnie Freeman, Brent Patel, Rohit van Ginkel, Charlotte Koepsell, Hermann Busslinger, Meinrad Onishi, Akira Nespoux, Josselin Vallon, Volker eng R01 DK112042/DK/NIDDK NIH HHS/ R01 DK106102/DK/NIDDK NIH HHS/ P30 DK079337/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2018/11/15 Am J Physiol Renal Physiol. 2019 Jan 1;316(1):F173-F185. doi: 10.1152/ajprenal.00462.2018. Epub 2018 Nov 14.}, number = 1, pages = {F173-F185}, timestamp = {2024-02-15T15:08:22.000+0100}, title = {SGLT2 inhibition and renal urate excretion: role of luminal glucose, GLUT9, and URAT1}, type = {Journal Article}, url = {https://www.ncbi.nlm.nih.gov/pubmed/30427222}, volume = 316, year = 2019 }