Luminal and basolateral mechanisms involved in the renal tubular uptake of inorganic mercury

Abstract

The principle aim of the present study was to provide evidence for the existence of both a luminal and a basolateral mechanism involved in the renal tubular uptake of inorganic mercury. To accomplish this aim, we examined individually and collectively the effects of a "stop-flow" technique designed to reduce glomerular filtration to negligible levels and pretreatment with the organic anion p-aminohippurate (PAH) on the renal uptake and disposition of administered inorganic mercury. More specifically, we compared the disposition of inorganic mercury in groups of surgical control rats, rats that underwent a unilateral ureteral ligation, and rats that underwent a bilateral ureteral ligation that were pretreated with either normal saline or a 7.5 mmol/kg intravenous dose of PAH 5 min prior to receiving a nontoxic 0.5-mumol/kg intravenous dose of mercuric chloride. The disposition of mercury was evaluated at both 1 h and 24 h after the dose of inorganic mercury had been administered. In brief, the "stop-flow" conditions induced by either unilateral or bilateral ureteral ligation caused a significant reduction in the uptake and content of mercury in the kidneys (whose ureter was ligated) both at 1 h and 24 h after the intravenous injection of the nontoxic dose of mercuric chloride. This decreased renal uptake of mercury was due specifically to decreased uptake of mercury in the renal cortex and outer stripe of the outer medulla. Assuming that glomerular filtration was reduced to negligible levels, the amount of mercury not taken up during ureteral ligation represents the portion of mercury that is presumably taken up by a luminal mechanism. Pretreatment with PAH also caused a significant reduction in the renal uptake of mercury, specifically in the cortex and outer stripe of the outer medulla. The effects were most prominent 1 h after the injection of inorganic mercury. When either unilateral or bilateral ureteral ligation was combined with PAH pretreatment, an additive inhibitory effect occurred with respect to the renal uptake of mercury. In fact, the renal uptake of mercury was reduced by approximately 85% at 1 h after the injection of mercuric chloride. Since the luminal uptake of mercury was blocked by ureteral ligation, the effect of PAH on the renal uptake of mercury must have occurred at the basolateral membrane. Thus, the findings from the present study indicate that there are two distinct mechanisms involved in the uptake of mercury, with one mechanism located on the luminal membrane and another located on the basolateral membrane (presumably on proximal tubular epithelial cells).

The Renal Na+-Dependent Dicarboxylate Transporter, NaDC-3, Translocates Dimethyl- and Disulfhydryl-Compounds and Contributes to Renal Heavy Metal Detoxification

“…Similar results with respect to DMPS and HgCl 2 were obtained in isolated S2-segments of rabbits (32). In the isolated, perfused rat kidney (33), net tubular secretion of DMPS was saturable and blocked by p-aminohippurate and probenecid, substrate and inhibitor of the organic anion/dicarboxylate exchanger, OAT1. In rat kidney in situ, DMPS inhibited radiolabeled PAH uptake, but not dimethylsuccinate uptake (34).…”

“…mercury. The DMSA-heavy metal complex must leave the proximal tubule cell via the luminal membrane, probably by MRP2 (50,51), peptide-and amino acid-transporting proteins (33), or by other as yet unknown transporters.…”

Molecular and ionic mimicry and the transport of toxic metals

“…In experiments where the rates of glomerular filtration in rats were reduced to negligible levels, a 40% decrease in the renal tubular uptake of Hg 2+ was observed, indicating that the basolateral uptake of Hg 2+ comprises a significant fraction of the total renal uptake of Hg 2+ (Zalups and Minor, 1995). Data from these experiments also demonstrated that the addition of para-aminohippurate (PAH), which is a specific inhibitor of the organic anion transporter (OAT) family (Ferrier et al, 1983;Pritchard, 1988;Roch-Ramel et al, 1992;Shimomura et al, 1981;Ullrich et al, 1987aUllrich et al, , 1998b, effectively inhibited Hg 2+ uptake.…”

“…Recent studies provide strong evidence indicating that there are at least two distinct mechanisms (or sets of mechanisms) responsible for the uptake of Hg in proximal tubular cells: at least one localized in the luminal membrane Zalups, 1995Zalups, , 1997Zalups, , 1998aZalups, , 1998bBarfuss, 1993b, 1998a;Zalups and Minor, 1995;Zalups and Lash, 1997b;Zalups et al, 1991Zalups et al, , 1998 and at least another one in the basolateral membrane (Aslamkhan et al, 2003;Zalups, 1995Zalups, , 1997Zalups, , 1998aZalups and Barfuss, 1993b, 1998aZalups and Lash, 1997b;Zalups and Minor, 1995;.…”

“…In addition to the uptake of Hg 2+ at the luminal plasma membrane, a preponderance of evidence indicates that approximately 40−60% of the proximal tubular uptake of Hg 2+ occurs via one or more transporters located at the basolateral membrane (Zalups, 1995(Zalups, , 1997(Zalups, , 1998a(Zalups, , 1998bZalups and Barfuss, 1995, 1998a, 1998bZalups and Minor, 1995). In experiments where the rates of glomerular filtration in rats were reduced to negligible levels, a 40% decrease in the renal tubular uptake of Hg 2+ was observed, indicating that the basolateral uptake of Hg 2+ comprises a significant fraction of the total renal uptake of Hg 2+ (Zalups and Minor, 1995).…”