2007 JASN IMPACT FACTOR 7.111	HOME   AUTHOR INFO   EDITORIAL BOARD   SUBSCRIBE   FEEDBACK   ALERTS   HELP
advanced	CURRENT ISSUE	ARCHIVES	JASN Express	ONLINE SUBMISSION

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by ÇCetinkaya, I. Articles by Kleta, R. Search for Related Content PubMed PubMed Citation Articles by ÇCetinkaya, I. Articles by Kleta, R.

Inhibition of Na⁺-Dependent Transporters in Cystine-Loaded Human Renal Cells: Electrophysiological Studies on the Fanconi Syndrome of Cystinosis

Ibrahim ÇCetinkaya^*,, Eberhard Schlatter, Jochen R. Hirsch, Peter Herter, Erik Harms^* and Robert Kleta^*

* Department of Pediatrics, University Children’s Hospital Muenster, Muenster, Germany; Department of Internal Medicine D, Experimental Nephrology, University Hospital Muenster, Muenster, Germany; Max-Planck-Institute for Molecular Physiology, Dartmund, Germany.

Correspondence to Dr. Eberhard Schlatter, Universitaetsklinikum Münster, Medizinische Klinik und Poliklinik D, Experimentelle Nephrologie, Domagkstrasse 3A, 48149 Münster, Germany. Phone: 49-251-83-56991; 49-251-83-56973; E-mail: eberhard.schlatter{at}uni-muenster.de

ABSTRACT. Cystinosis is the most common cause of the renal Fanconi syndrome in children, leading to severe electrolyte disturbances and growth failure. A defective lysosomal transporter, cystinosin, results in intralysosomal accumulation of cystine. Loading cells with cystine dimethyl ester (CDME) is the only available model for this disease. This model was used to present electrophysiologic studies on immortalized human kidney epithelial (IHKE-1) cells that had been derived from the proximal tubule with the slow whole-cell patch clamp technique. Basal membrane voltages (V_m) of IHKE-1 cells were -30.7 ± 0.4 mV (n = 151). CDME concentration-dependently altered V_m with an initial depolarization (2.7 ± 0.2 mV;n = 76; 1 mM CDME) followed by a more pronounced hyperpolarization (-9.9 ± 1.0 mV;n = 49). Three Na⁺-dependent transporters were examined. Alanine (1 mM) depolarized IHKE-1 cells by 17.6 ± 0.7 mV (n = 59), and phosphate (1.8 mM) depolarized by 9.7 ± 1.1 mV (n = 18). Acidification of IHKE-1 cells with propionate (20 mM) resulted in a depolarization of V_m by 7.1 ± 0.3 mV (n = 21) followed by a repolarization by 2.9 ± 0.3 mV/min (n = 17), reflecting Na⁺/H⁺-exchanger activity. Acute addition of 1 mM CDME did not alter the alanine- and propionate-induced changes in V_m, but it reduced the phosphate-induced depolarization by 37 ± 9% (n = 10). Incubation with 1 mM CDME reduced the activity of all three transporters. Depolarizations by alanine and phosphate and the repolarization after propionate were inhibited by 57 ± 4% (n =30), 45 ± 9% (n = 9), and 78 ± 15% (n = 8), respectively. In conclusion, this study demonstrates that CDME acutely alters V_m of IHKE-1 cells and that at least three Na⁺-dependent transporters are inhibited, the Na⁺-phosphate cotransporter most sensitively. This might suggest that phosphate depletion and dissipation of the Na⁺-gradient are involved in the development of the Fanconi syndrome of cystinosis.

This article has been cited by other articles:

				A. Thirumurugan, A. Thewles, R. D. Gilbert, S.-A. Hulton, D. V. Milford, C. J. Lote, and C. M. Taylor Urinary L-lactate excretion is increased in renal Fanconi syndrome Nephrol. Dial. Transplant., July 1, 2004; 19(7): 1767 - 1773. [Abstract] [Full Text] [PDF]

				M. Park, A. Helip-Wooley, and J. Thoene Lysosomal Cystine Storage Augments Apoptosis in Cultured Human Fibroblasts and Renal Tubular Epithelial Cells J. Am. Soc. Nephrol., December 1, 2002; 13(12): 2878 - 2887. [Abstract] [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673