Role of organic anion and amino acid carriers in transport of inorganic mercury in rat renal basolateral membrane vesicles: Influence of compensatory renal growth

Abstract

Susceptibility to renal injury induced by inorganic mercury (Hg2+) increases significantly as a result of compensatory renal growth (following reductions of renal mass). We hypothesize that this phenomenon is related in part to increased basolateral uptake of Hg2+ by proximal tubular cells. To determine the mechanistic roles of various transporters, we studied uptake of Hg2+, in the form of biologically relevant Hg2+-thiol conjugates, using basolateral membrane (BLM) vesicles isolated from the kidney(s) of control and uninephrectomized (NPX) rats. Binding of Hg2+ to membranes, accounted for 52-86% of total Hg2+ associated with membrane vesicles exposed to HgCl2, decreased with increasing concentrations of HgCl2, and decreased slightly in the presence of sodium ions. Conjugation of Hg2+ with thiols (glutathione, L-cysteine (Cys), N-acetyl-L-cysteine) reduced binding by more than 50%. Under all conditions, BLM vesicles from NPX rats exhibited a markedly lower proportion of binding. Of the Hg2+ -thiol conjugates studied, transport of Hg-(Cys)2 was fastest. Selective inhibition of BLM carriers implicated the involvement of organic anion transporter(s) (Oat1 and/or Oat3; Slc22a6 and Slc22a8), amino acid transporter system ASC (Slc7a10), the dibasic amino acid transporter (Slc3a1), and the sodium-dicarboxylate carrier (SDCT2 or NADC3; Slc13a3). Uptake of each mercuric conjugate, when factored by membrane protein content, was higher in BLM vesicles from uninephrectomized (NPX) rats, with specific increases in transport by the carriers noted above. These results support the hypothesis that compensatory renal growth is associated with increased uptake of Hg2+ in proximal tubular cells and we have identified specific transporters involved in the process. © The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.