P-glycoprotein (P-gp) is an
ATP-dependent transporter localized at the apical membrane of the kidney proximal tubules, which plays a role in the efflux of cationic and amphipathic endogenous
waste products and
xenobiotics, such as drugs, into urine. Studies in mice deficient in P-gp showed generalized proximal tubular dysfunction similar to the phenotype of patients with
cystinosis, an autosomal recessive disorder caused by mutations in the lysosomal
cystine transporter cystinosin. Renal disease in
cystinosis is characterized by generalized dysfunction of the apical proximal tubular influx transporters (so-called
renal Fanconi syndrome) developing during infancy and gradually progressing towards
end-stage renal disease before the 10th birthday in the majority of patients that are not treated with the
cystine-depleting
drug cysteamine. Here, we investigated whether the proximal tubular efflux transporter P-gp is affected in
cystinosis and whether this might contribute to the development of
renal Fanconi syndrome. We used conditionally immortalized (ci) proximal tubular epithelial cells (ciPTEC) derived from cystinotic patients and healthy volunteers. P-gp-mediated transport was measured by using the P-gp substrate
calcein-AM in the presence and absence of the P-gp-inhibitor
PSC833. P-gp activity was normal in cystinotic cells as compared to controls. Additionally, the effect of
cysteamine on P-gp transport activity and
phosphate uptake was determined; demonstrating increased P-gp activity in cystinotic cells, and further decrease of proximal tubular
phosphate uptake. This observation is compatible with the persistence of
renal Fanconi syndrome in vivo under
cysteamine therapy. In summary, P-gp expression and activity are normal in cystinotic ciPTEC, indicating that P-gp dysfunction is not involved in the pathogenesis of
cystinosis.