Cationic uremic toxins affect human renal proximal tubule cell functioning through interaction with the organic cation transporter
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SourcePflügers Archiv : European Journal of Physiology, 465, 12, (2013), pp. 1701-1714
Article / Letter to editor
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Paediatrics - OUD tm 2017
Laboratory of Genetic, Endocrine and Metabolic Diseases
Pflügers Archiv : European Journal of Physiology
SubjectIGMD 3: Genomic disorders and inherited multi-system disorders NCMLS 4: Energy and redox metabolism; IGMD 8: Mitochondrial medicine NCMLS 4: Energy and redox metabolism; IGMD 9: Renal disorder; IGMD 9: Renal disorder NCMLS 4: Energy and redox metabolism; IGMD 9: Renal disorder NCMLS 5: Membrane transport and intracellular motility; NCMLS 5: Membrane transport and intracellular motility IGMD 9: Renal disorder; IGMD 8: Mitochondrial medicine NCMLS 4: Energy and redox metabolism; IGMD 9: Renal disorder NCMLS 5: Membrane transport and intracellular motility
Several organic cations, such as guanidino compounds and polyamines, have been found to accumulate in plasma of patients with kidney failure due to inadequate renal clearance. Here, we studied the interaction of cationic uremic toxins with renal organic cation transport in a conditionally immortalized human proximal tubule epithelial cell line (ciPTEC). Transporter activity was measured and validated in cell suspensions by studying uptake of the fluorescent substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium-iodide (ASP(+)). Subsequently, the inhibitory potencies of the cationic uremic toxins, cadaverine, putrescine, spermine and spermidine (polyamines), acrolein (polyamine breakdown product), guanidine, and methylguanidine (guanidino compounds) were determined. Concentration-dependent inhibition of ASP(+) uptake by TPA, cimetidine, quinidine, and metformin confirmed functional endogenous organic cation transporter 2 (OCT2) expression in ciPTEC. All uremic toxins tested inhibited ASP(+) uptake, of which acrolein required the lowest concentration to provoke a half-maximal inhibition (IC50 = 44 +/- 2 muM). A Dixon plot was constructed for acrolein using three independent inhibition curves with 10, 20, or 30 muM ASP(+), which demonstrated competitive or mixed type of interaction (K i = 93 +/- 16 muM). Exposing the cells to a mixture of cationic uremic toxins resulted in a more potent and biphasic inhibitory response curve, indicating complex interactions between the toxins and ASP(+) uptake. In conclusion, ciPTEC proves a suitable model to study cationic xenobiotic interactions. Inhibition of cellular uptake transport was demonstrated for several uremic toxins, which might indicate a possible role in kidney disease progression during uremia.
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