Intracellular cystine loading inhibits transport in the rabbit proximal convoluted tubule.

Salmon, Richard F.; Baum, Michel

doi:10.1172/jci114443

Cited by 37 publications

(44 citation statements)

References 17 publications

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“…So far with this model uptake measurements with radiolabeled solutes were performed in rat (10,18,31,34) and rabbit (11,13,14,32,33) proximal tubules and with cultured porcine LLC-PK 1 cells (15,19,30). These studies showed an inhibition of volume absorption (13,14), reduction of the transepithelial potential difference (13), and inhibition of transport of different solutes (7,10,(13)(14)(15). Most of proximal tubular transport is Na ϩ -coupled; depending therefore on the Na ϩ -gradient from the extrato the intracellular space, the role of energy metabolism, Na ϩ / K ϩ -ATPase activity, intracellular phosphate, and ATP levels in this experimental model have been investigated (14,18,31,33,34).…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition of volume reabsorption and a decrease in the lumen-negative transepithelial potential difference were shown under these conditions (13,14). Furthermore, inhibition of glucose, different amino acids, bicarbonate, and phosphate reabsorption in cystine-loaded proximal tubules was demonstrated (7,13). Inhibition of glucose transport was also shown in LLC-PK 1 cells (15).…”

mentioning

confidence: 87%

“…Sakarcan et al (11) showed that cystine in this model is mainly accumulated intralysosomally. So far, uptake measurements of radiolabeled substances by rat and rabbit proximal tubules and by porcine proximal tubular cells (LLC-PK 1 ) have been used to obtain insights into the pathophysiologic mechanisms of the Fanconi syndrome of cystinosis (7,10,(13)(14)(15). Inhibition of volume reabsorption and a decrease in the lumen-negative transepithelial potential difference were shown under these conditions (13,14).…”

mentioning

confidence: 99%

“…So far, uptake measurements of radiolabeled substances by rat and rabbit proximal tubules and by porcine proximal tubular cells (LLC-PK 1 ) have been used to obtain insights into the pathophysiologic mechanisms of the Fanconi syndrome of cystinosis (7,10,(13)(14)(15). Inhibition of volume reabsorption and a decrease in the lumen-negative transepithelial potential difference were shown under these conditions (13,14). Furthermore, inhibition of glucose, different amino acids, bicarbonate, and phosphate reabsorption in cystine-loaded proximal tubules was demonstrated (7,13).…”

mentioning

confidence: 99%

“…Corresponding to the decreased glucose uptake, cystine loading resulted in a reduced number of glucose transporters on the apical membrane of LLC-PK 1 cells (15) and in brush border membrane vesicles from rats after intraperitoneal CDME injections (16). Salmon et al (13) used the CDME model to show that reduction in proximal tubular transport was due to an inhibition of active transport but not to an increase in proximal tubular permeability, as it was previously supposed for the Fanconi syndrome caused by maleic acid (17). Most of proximal tubular transport of solutes across the luminal membrane is secondarily coupled with active Na ϩ -transport; studies were therefore performed to investigate the relationship between intracellular cystine accumulation and energy metabolism.…”

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confidence: 99%

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Inhibition of Na+-Dependent Transporters in Cystine-Loaded Human Renal Cells

Çetinkaya¹,

Schlatter²,

Hirsch³

et al. 2002

Journal of the American Society of Nephrology

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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 Ϫ30.7 Ϯ 0.4 mV (n ϭ 151). CDME concentration-dependently altered V m with an initial depolarization (2.7 Ϯ 0.2 mV; n ϭ 76; 1 mM CDME) followed by a more pronounced hyperpolarization (Ϫ9.9 Ϯ 1.0 mV; n ϭ 49). Three Na ϩ -dependent transporters were examined. Alanine (1 mM) depolarized IHKE-1 cells by 17.6 Ϯ 0.7 mV (n ϭ 59), and phosphate (1.8 mM) depolarized by 9.7 Ϯ 1.1 mV (n ϭ 18).Acidification of IHKE-1 cells with propionate (20 mM) resulted in a depolarization of V m by 7.1 Ϯ 0.3 mV (n ϭ 21) followed by a repolarization by 2.9 Ϯ 0.3 mV/min (n ϭ 17), reflecting Na ϩ /H ϩ -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 Ϯ 9% (n ϭ 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 Ϯ 4% (n ϭ 30), 45 Ϯ 9% (n ϭ 9), and 78 Ϯ 15% (n ϭ 8), respectively. In conclusion, this study demonstrates that CDME acutely alters V m of IHKE-1 cells and that at least three Na ϩ -dependent transporters are inhibited, the Na ϩ -phosphate cotransporter most sensitively. This might suggest that phosphate depletion and dissipation of the Na ϩ -gradient are involved in the development of the Fanconi syndrome of cystinosis.

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