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Cationic uremic toxins affect human renal proximal tubule cell functioning through interaction with the organic cation transporter

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Author

  • Carolien M. S. Schophuizen
  • Martijn J. Wilmer
  • Jitske Jansen
  • Lena Gustavsson
  • Constanze Hilgendorf
  • Joost G. J. Hoenderop
  • Lambert P. van den Heuvel
  • Rosalinde Masereeuw

Summary, in English

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 mu M). A Dixon plot was constructed for acrolein using three independent inhibition curves with 10, 20, or 30 mu M ASP(+), which demonstrated competitive or mixed type of interaction (K (i) = 93 +/- 16 mu M). 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.

Publishing year

2013

Language

English

Pages

1701-1714

Publication/Series

Pflügers Archiv

Volume

465

Issue

12

Document type

Journal article

Publisher

Springer

Topic

  • Cancer and Oncology

Keywords

  • Human proximal tubule cell
  • OCT
  • Uremic toxin
  • Polyamines
  • Guanidine
  • Acrolein

Status

Published

ISBN/ISSN/Other

  • ISSN: 0031-6768