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Cl^–-dependent upregulation of human organic anion transporters: different effects on transport kinetics between hOAT1 and hOAT3

Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, Japan

Submitted 18 September 2006 ; accepted in final form 8 April 2007

Chloride ion has a stimulatory effect on the transport of organic anions across renal basolateral membranes. However, the exact mechanisms at molecular levels have been unclear as of yet. Human organic anion transporters hOAT1 and hOAT3 play important roles in renal basolateral membranes. In this study, the effects of Cl^– on the activities of these transporters were evaluated by using HEK293 cells stably expressing hOAT1 or hOAT3 (HEK-hOAT1 or HEK-hOAT3). The uptake of p-[¹⁴C]aminohippurate by HEK-hOAT1 and [³H]estrone sulfate by HEK-hOAT3 was greater in the presence of Cl^– than in the presence of SO₄^2– or gluconate. Additionally, the uptake of various compounds by HEK-hOAT1 and HEK-hOAT3 was significantly higher in the Cl^–-containing medium than the gluconate-containing medium, suggesting that the influences of Cl^– are not dependent on substrate and that Cl^– directly stimulates the functions of hOAT1 and hOAT3. The substitution of gluconate with Cl^– did not change the K_m value for the uptake of p-[¹⁴C]aminohippurate by HEK-hOAT1 but caused an approximately threefold increase in the maximal uptake rate (V_max) value. On the other hand, replacement of gluconate with Cl^– decreased the K_m value for the uptake of [³H]estrone sulfate and cefotiam by HEK-hOAT3 to about one-third, while it did not change the V_max value. In summary, Cl^– upregulates the activities of both hOAT1 and hOAT3, but its effects on transport kinetics differ between these transporters. It was suggested that Cl^– participates in the trans-location process for hOAT1, and the substrate recognition process for hOAT3.

renal secretion; basolateral membrane; SLC22A; HEK293