Abstract
During chronic kidney disease (CKD), there is a progressive accumulation of toxic solutes due to inadequate renal clearance. Here, the interaction between uremic toxins and two important efflux pumps, viz. multidrug resistance protein 4 (MRP4) and breast cancer resistance protein (BCRP) was investigated. Membrane vesicles isolated from MRP4- or BCRP-overexpressing human embryonic kidney cells were used to study the impact of uremic toxins on substrate specific uptake. Furthermore, the concentrations of various uremic toxins were determined in plasma of CKD patients using high performance liquid chromatography and liquid chromatography/tandem mass spectrometry. Our results show that hippuric acid, indoxyl sulfate and kynurenic acid inhibit MRP4-mediated [3H]-methotrexate ([3H]-MTX) uptake (calculated Ki values: 2.5 mM, 1 mM, 25 µM, respectively) and BCRP-mediated [3H]-estrone sulfate ([3H]-E1S) uptake (Ki values: 4 mM, 500 µM and 50 µM, respectively), whereas indole-3-acetic acid and phenylacetic acid reduce [3H]-MTX uptake by MRP4 only (Ki value: 2 mM and IC50 value: 7 mM, respectively). In contrast, p-cresol, p-toluenesulfonic acid, putrescine, oxalate and quinolinic acid did not alter transport mediated by MRP4 or BCRP. In addition, our results show that hippuric acid, indole-3-acetic acid, indoxyl sulfate, kynurenic acid and phenylacetic acid accumulate in plasma of end-stage CKD patients with mean concentrations of 160 µM, 4 µM, 129 µM, 1 µM and 18 µM, respectively. Moreover, calculated Ki values are below the maximal plasma concentrations of the tested toxins. In conclusion, this study shows that several uremic toxins inhibit active transport by MRP4 and BCRP at clinically relevant concentrations.
Highlights
5% of the adult population in the developed countries suffers from chronic kidney disease (CKD) stage III-V, which is defined by a decreased estimated glomerular filtration rate [1]
This study reports, for the first time, that several uremic toxins directly inhibit transport by two important efflux pumps, viz
Since multidrug resistance protein 4 (MRP4) and breast cancer resistance protein (BCRP) are located at the apical membrane of proximal tubule cells, transport activity depends on the intracellular levels of substrates rather than substrate concentrations in the blood
Summary
5% of the adult population in the developed countries suffers from chronic kidney disease (CKD) stage III-V, which is defined by a decreased estimated glomerular filtration rate (eGFR) [1]. A main feature at this stage of CKD is the accumulation of solutes that are normally excreted in urine These uremic retention solutes, known as uremic toxins, are a heterogeneous group of organic compounds. (2) The middle molecules, with a MW .500 Da, such as b2-microglobulin; due to their size, these retention solutes can only be cleared using dialyzer membranes with large pores, which focus on filtration via convection instead of diffusion. (3) The proteinbound solutes; the compounds in this group mostly have a small MW and prototypes include indoxyl sulfate and p-cresol sulfate Solutes belonging to this group are very difficult to clear using current dialysis strategies and they exhibit toxic effects [2]. Understanding the endogenous clearance of protein-bound solutes could lead to the development of novel therapeutic strategies for the removal of uremic toxins
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