Aminoglycoside antibiotics reduce glucose reabsorption in kidney through down-regulation of SGLT1.
Nephrotoxicity is known to be a major clinical side effect of aminoglycoside antibiotics. Aminoglycosides cause damage to proximal tubular cells in kidney, however the mechanism of toxicity is still unclear. In order to elucidate the mechanism of nephrotoxicity, we studied the effect of aminoglycoside antibiotics on glucose transport systems in vitro and in vivo. As a result, we found that the aminoglycosides significantly reduced Na(+)/glucose cotransporter (SGLT1)-dependent glucose transport and also down-regulated mRNA and protein levels of the SGLT1 in pig proximal tubular LLC-PK(1) cells. To obtain evidence about SGLT1 down-regulation in vivo, we studied the mRNA expression of SGLT1 using gentamicin C-treated murine kidney and found that gentamicin C down-regulated SGLT1 in vivo as well as in vitro. Furthermore, the gentamicin C-treated mice showed significant rise in urinary glucose excretion. These results indicate that one of the mechanisms of aminoglycoside nephrotoxicity is the down-regulation of SGLT1, which causes reduction in glucose reabsorption in kidney.
Takamoto
Kozo
K
Microbial Chemistry Research Center, Numazu Bio-Medical Research Institute, 18-24 Miyamoto, Numazu-shi, Shizuoka 410-0301, Japan.
Kawada
Manabu
M
Usui
Takayuki
T
Ishizuka
Masaaki
M
Ikeda
Daishiro
D
D000617:Aminoglycosides / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001692:Biological Transport; D002460:Cell Line; D002478:Cells, Cultured; D003404:Creatinine / Q000652:urine; D015536:Down-Regulation; D005260:Female; D005839:Gentamicins / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D006601:Hexoses / Q000378:metabolism; D015151:Immunoblotting; D007668:Kidney / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D009004:Monosaccharide Transport Proteins / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051269:Sodium-Glucose Transporter 1; D013552:Swine
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D005839:Gentamicins; D006601:Hexoses; D008562:Membrane Glycoproteins; D009004:Monosaccharide Transport Proteins; D012333:RNA, Messenger; C495675:Slc5a1 protein, mouse; D051269:Sodium-Glucose Transporter 1; C100093:gentamicin C; D003404:Creatinine; D005947:Glucose