Sulfated bile acids inhibit Na(+)-H+ antiport in human kidney brush-border membrane vesicles

Abstract

Patients with obstructive jaundice are at a high risk for acute renal failure after surgery. Direct toxic membrane effects of bile acids or bilirubin have been discussed as possible causes. Therefore, we investigated the influence of bile acids and conjugated bilirubin on Na(+)-H+ antiport and ion permeabilities in brush-border membrane vesicles isolated from the human kidney. Brush-border membrane vesicles were prepared by Mg2+ precipitation. These were highly purified as estimated from the 14-fold enrichment in the specific activity of alanine aminopeptidase. The pH-sensitive dye acridine orange was used to study the properties of proton uptake under different conditions. The brush-border membrane vesicles from human kidney cortex exhibited Na+ and K+ conductances, which were small compared with H+ conductance. Furthermore, these membranes possess an Na(+)-H+ antiporter that is sensitive to amiloride. Various bile acids (30 microM) had no significant effect on Na(+)-H+ antiport. However, the addition of sulfated bile acids resulted in a significant inhibition (greater than 50%) of the Na(+)-H+ antiporter. A nonspecific effect of sulfated bile acids on the vesicles was excluded by the use of ionophores to determine vesicle integrity and to estimate the various ion conductances. Therefore specific inhibition of the human renal Na(+)-H+ antiporter by sulfated bile acids occurs. This could result in an impaired cellular pH regulation and might play a role in postoperative acute renal failure in patients with obstructive jaundice.