Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The renal proximal tubule is a major site of injury in a variety of congenital/metabolic diseases including nephropathic cystinosis, the most commonly known cause of renal Fanconi's syndrome. In this lysosomal storage disease there are defects in proximal tubule function within the first few months of life. While culture of renal tubular cells from the urine of these patients is possible, development of immortalized cell lines would insure large numbers of homogeneous cells for studies of renal epithelial cell morphology and pathophysiology in this disease. To develop immortalized cells, cystinotic and normal proximal tubular cells in culture were exposed to an immortalizing vector, containing pZiptsU19 with the temperature sensitive SV40 T-antigen allele tsA58U19 and a neomycin resistance gene, and neomycin-resistant tubular cells were selected for propagation. Ten clones from cystinotic patients have been developed and characterized. All clones express T-antigen at permissive temperature (33 degrees C). Immortalized cells have an epithelial morphology and grow to form confluent monolayers; doubling times vary from 31 to 86 hours. Cystinotic clones are keratin, MDR P-glycoprotein, and alpha-95 kD brush-border associated protein positive but Tamm-Horsfall protein negative by immunocytochemistry, as are normal proximal tubule cells immortalized with this vector. This is consistent with a proximal tubule origin of the cystinotic clones. The cystine content of the cystinotic cells is 70 to 160 times that of normal renal proximal tubular cells in culture, with most of the cystine sequestered in cell lysosomes, confirming that these cell lines express the storage defect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Renal proximal tubular epithelium from patients with nephropathic cystinosis: immortalized cell lines as in vitro model systems. 756 23

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.
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PMID:Role of p-glycoprotein expression and function in cystinotic renal proximal tubular cells. 2430 8