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ToxSci Advance Access originally published online on September 14, 2005
Toxicological Sciences 2005 88(2):630-644; doi:10.1093/toxsci/kfi328
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Role of Organic Anion and Amino Acid Carriers in Transport of Inorganic Mercury in Rat Renal Basolateral Membrane Vesicles: Influence of Compensatory Renal Growth

Lawrence H. Lash*,1, Sarah E. Hueni*, David A. Putt* and Rudolfs K. Zalups{dagger}

* Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan 48201; {dagger} Division of Basic Medical Sciences, Mercer University School of Medicine, Macon, Georgia 31207

Received July 28, 2005; accepted September 13, 2005

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.

Key Words: Mercury-thiol conjugates; kidney; basolateral membrane vesicles; transport; organic anion transporters; amino acid transporters; compensatory renal growth.


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L. H. Lash, D. A. Putt, and R. K. Zalups
Influence of Compensatory Renal Growth on Susceptibility of Primary Cultures of Renal Cells to Chemically Induced Injury
Toxicol. Sci., December 1, 2006; 94(2): 417 - 427.
[Abstract] [Full Text] [PDF]


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