Role of P-Glycoprotein Expression and Function in Cystinotic Renal Proximal Tubular Cells

Pharmaceutics

Karen Peeters²  Martijn J. Wilmer³  Joost P. Schoeber²  Dorien Reijnders¹  Lambertus P. van den Heuvel²  Rosalinde Masereeuw³ 

[1] Department of Pediatrics, Radboud University Nijmegen Medical Center, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands;Pediatric Nephrology, Katholieke Universiteit Leuven, Herestraat 49 Box 817, Leuven, Belgium;Department of Pharmacology and Toxicology (149), Radboud University Nijmegen Medical Center, Geert Grooteplein Noord 21, 6525 GA, Nijmegen, The Netherlands

关键词: cystinosis;    P-glycoprotein;    renal proximal tubular cell;    cysteamine;   

DOI  :  10.3390/pharmaceutics3040782

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2011 by the authors; licensee MDPI, Basel, Switzerland.