Deletion of Multispecific Organic Anion Transporter Oat1/Slc22a6 Protects against Mercury-induced Kidney Injury

Abstract

The primary site of mercury-induced injury is the kidney due to uptake of the reactive Hg 2؉ -conjugated organic anions in the proximal tubule. Here, we investigated the in vivo role of Oat1 (organic anion transporter 1; originally NKT (Lopez-Nieto, C. E., You, G., Bush, K. T., Barros, E. J., Beier, D. R., and Nigam, S. K. (1997) J. Biol. Chem. 272, 6471-6478)) in handling of known nephrotoxic doses of HgCl 2 . Oat1 (Slc22a6) is a multispecific organic anion drug transporter that is expressed on the basolateral aspects of renal proximal tubule cells and that mediates the initial steps of elimination of a broad range of endogenous metabolites and commonly prescribed pharmaceuticals. Mercury-induced nephrotoxicity was observed in a wild-type model. We then used the Oat1 knock-out to determine in vivo whether the renal injury effects of mercury are mediated by Oat1. Most of the renal injury (both histologically and biochemically as measured by blood urea nitrogen and creatinine) was abolished following HgCl 2 treatment of Oat1 knock-outs. Thus, acute kidney injury by HgCl 2 was found to be mediated mainly by Oat1. Our findings raise the possibility that pharmacological modulation of the expression and/or function of Oat1 might be an effective therapeutic strategy for reducing renal injury by mercury. This is one of the most striking phenotypes so far identified in the Oat1 knock-out. (Eraly, S. A.,

Amelioration of mercury nephrotoxicity after pharmacological manipulation of organic anion transporter 1 (Oat1) and multidrug resistance-associated protein 2 (Mrp2) with furosemide

“…We have recently demonstrated that most of the renal injury induced by HgCl 2 was abolished following HgCl 2 treatment of Oat1 knock-out mice 11 . Thus, HgCl 2 induced AKI was found to be mediated mainly by Oat1.…”

“…on the 4 th day. Experiments were performed after 18 h of HgCl 2 injection as previously described 7,11,15,27 .…”

“…Torres et al 11 have demonstrated, using Oat1 knock-out mice, that HgCl 2 induced AKI is mediated mainly by Oat1. In addition, since female rats express lower levels of renal cortical Oat1 than males 12-14 , Hazelhoff et al 15 have recently observed that mercury-induced renal damage is reduced in female rats as compared with males.…”

Kidney versus Liver Specification of SLC and ABC Drug Transporters, Tight Junction Molecules, and Biomarkers

“…This requires establishment of a permeability barrier (mediated by tight junctions), expression of appropriate ABC and SLC drug and solute transporters, as well as drug-metabolizing enzymes. For example, the major transporter of many organic anion drugs, toxins, and metabolites, OAT1 (originally identified as NKT) must be expressed on the basolateral surface of the proximal tubule cell (Lopez-Nieto et al, 1997;Nigam et al, 2015b;Wu et al, 2015;Zhu et al, 2015); when this gene is deleted, there is considerable loss of renal transport of many organic anion drugs, toxins, and metabolites (Eraly et al, 2006;Truong et al, 2008;Nagle et al, 2011;Torres et al, 2011;Wikoff et al, 2011). Although there is some commonality of expressed genes, they are often differentially expressed.…”

Hepatocyte Nuclear Factors 4αand 1αRegulate Kidney Developmental Expression of Drug-Metabolizing Enzymes and Drug Transporters

“…Based on in vitro and in vivo knockout data, this is generally believed to be the main pathway for kidney elimination of many common drugs (e.g., antibiotics, antivirals, diuretics, nonsteroidal anti-inflammatory drugs) and toxins (e.g., mercury conjugates) (VanWert et al, 2010;Torres et al, 2011). This pathway has received increased attention given new FDA guidelines, and its role in neonatal drug handling is of considerable interest.…”