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PLoS One. 2014 Sep 30;9(9):e108941. doi: 10.1371/journal.pone.0108941. eCollection 2014.

Sodium-glucose transporter-2 (SGLT2; SLC5A2) enhances cellular uptake of aminoglycosides.

Author information

1
Oregon Hearing Research Center, Oregon Health & Science University, Portland, Oregon, United States of America.
2
Oregon Hearing Research Center, Oregon Health & Science University, Portland, Oregon, United States of America; Department of Otorhinolaryngology, Seoul National University College of Medicine, Bundang Hospital, Seongnam, Gyeonggi, Republic of Korea.

Abstract

Aminoglycoside antibiotics, like gentamicin, continue to be clinically essential worldwide to treat life-threatening bacterial infections. Yet, the ototoxic and nephrotoxic side-effects of these drugs remain serious complications. A major site of gentamicin uptake and toxicity resides within kidney proximal tubules that also heavily express electrogenic sodium-glucose transporter-2 (SGLT2; SLC5A2) in vivo. We hypothesized that SGLT2 traffics gentamicin, and promotes cellular toxicity. We confirmed in vitro expression of SGLT2 in proximal tubule-derived KPT2 cells, and absence in distal tubule-derived KDT3 cells. D-glucose competitively decreased the uptake of 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG), a fluorescent analog of glucose, and fluorescently-tagged gentamicin (GTTR) by KPT2 cells. Phlorizin, an SGLT2 antagonist, strongly inhibited uptake of 2-NBDG and GTTR by KPT2 cells in a dose- and time-dependent manner. GTTR uptake was elevated in KDT3 cells transfected with SGLT2 (compared to controls); and this enhanced uptake was attenuated by phlorizin. Knock-down of SGLT2 expression by siRNA reduced gentamicin-induced cytotoxicity. In vivo, SGLT2 was robustly expressed in kidney proximal tubule cells of heterozygous, but not null, mice. Phlorizin decreased GTTR uptake by kidney proximal tubule cells in Sglt2+/- mice, but not in Sglt2-/- mice. However, serum GTTR levels were elevated in Sglt2-/- mice compared to Sglt2+/- mice, and in phlorizin-treated Sglt2+/- mice compared to vehicle-treated Sglt2+/- mice. Loss of SGLT2 function by antagonism or by gene deletion did not affect gentamicin cochlear loading or auditory function. Phlorizin did not protect wild-type mice from kanamycin-induced ototoxicity. We conclude that SGLT2 can traffic gentamicin and contribute to gentamicin-induced cytotoxicity.

PMID:
25268124
PMCID:
PMC4182564
DOI:
10.1371/journal.pone.0108941
[Indexed for MEDLINE]
Free PMC Article

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