Regulation of renal tubular bile acid transport in the early phase of an obstructive cholestasis in the rat

Background/Aims: In obstructive liver diseases, urinary excretion of bile acids is markedly enhanced. The mechanism of this effect is not entirely clear. The aim of the present study was to assess the glomerular and tubular factors involved in the renal handling of bile acids during the early phase of an obstructive cholestasis induced by a 24-hour bile duct ligation in rats. Methods: In addition to conventional clearance experiments, taurocholate transport was studied on proximal tubular cells freshly isolated from rat kidneys. The expression of the taurocholate transport protein was determined in these cells by immunoblotting. Results: Glomerular filtration rate and arterial blood pressure were not significantly affected by the cholestasis induced. The 3 H-taurocholate and 3 H-cholate clearances significantly increased whereas the fractional tubular reabsorption rates of these bile acids significantly fell. Probenecid did not affect the 3 H-taurocholate and 3 H-cholate clearances. By employing S0960, a specific inhibitor of the sodium-dependent bile salt transporter ASBT, it could be shown that this transporter mediates 3 H-taurocholate uptake into the proximal tubular cells. The bile duct ligation caused a significant decrease of the V max value of the taurocholate transporter indicating a downregulation of this transporter in cholestasis. The downregulation occurred without a change of the ASBT protein content of the proximal tubular cells. Conclusion: The results demonstrate that there is a functional adaptive downregulation of renal tubular bile acid transport enhancing renal clearance of bile acids during the early phase of an obstructive cholestasis.