Hydrogen peroxide downregulates human organic anion transporters in the basolateral membrane of the proximal tubule

Hydrogen peroxide (H2O2) is known to be involved in drug-induced and ischem ic proximal tubular damage. The purpose of this study was to elucidate the effects of hydrogen peroxide on organic anion transport mediated by human o rganic anion transporters 1 and 3 (hOAT1 and hOAT3), which are localized at the basolateral side of the proximal tubule. For this purpose, we establis hed and utilized the second segment of the proximal tubule cells from mice stably expressing hOAT1 or hOAT3 (S-2 hOAT1 or S-2 hOAT3, respectively). H2 O2 induced a dose- and a time-dependent decrease in organic anion transport mediated by hOAT1 and hOAT3. Kinetic analysis revealed that H2O2 decreased the Vmax, but not Km of organic anion transport both in S-2 hOAT1 and S-2 hOAT3. The effects of gentamicin, known to induce proximal tubular damage v ia the production of H2O2, on the organic anion transporters were also exam ined. Gentamicin induced a significant decrease in organic anion transport in S-2 hOAT1 but not S-2 hOAT3. H2O2-induced decrease in organic anion tran sport was significantly inhibited by pretreatment with pyruvate as well as catalase, whereas the gentamicin-induced decrease was significantly inhibit ed by pretreatment with pyruvate but not with catalase. In conclusion, thes e results suggest that H2O2, which is produced during tubular injuries, dow nregulates organic anion transport mediated by both hOAT1 and hOAT3, leadin g to further modulation of pathophysiology. (C) 2000 Elsevier Science Inc. All rights reserved.