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

Cadmium (Cd(2+)) is a non-essential heavy metal, which is taken up from the environment into the body through pulmonary and enteral pathways. The S1 segment of the kidney proximal tubule (PT) is a major target of chronic Cd(2+) toxicity. Renal dysfunction develops in up to 7% of the general population and in its most severe form displays major features of Fanconi syndrome, such as a defective protein, amino acid, glucose, bicarbonate and phosphate reabsorption. The major pathway for Cd(2+) uptake by PT cells (PTCs) in vivo is apical endocytosis of Cd(2+) complexed to the high-affinity metal-binding protein metallothionein (MT), which may be receptor-mediated. MT is subsequently degraded in endo-lysosomes, and Cd(2+) is liberated for translocation into the cytosolic compartment, possibly using transporters for Fe(2+), Zn(2+) or Cu(2+), such as the divalent metal transporter DMT1. Free Cd(2+) ions in the extracellular space are translocated across apical and/or basolateral PTC membranes into the cytosol via transporters, whose identity remains unknown. Cytosolic Cd(2+) generates reactive oxygen species (ROS), which deplete endogenous radical scavengers. ROS also damage a variety of transport proteins, including the Na(+)/K(+)-ATPase, which are subsequently degraded by the proteasome and endo-lysosomal proteases. Cd(2+) causes mitochondrial swelling and release of cytochrome C. If these ROS-mediated stress events are not balanced by repair processes, affected cells undergo apoptosis. But Cd(2+) also induces the upregulation of cytoprotective stress and metal-scavenging proteins, such as MT. In addition, Cd(2+) upregulates the detoxifying pump multidrug resistance P-glycoprotein, which appears to protect PTCs against Cd(2+)-induced apoptosis. Thus, Cd(2+) interferes with various cellular events ranging from mechanisms of induction of programmed cell death to activation of cell survival genes. A better understanding of the cellular mechanisms involved in Cd(2+) nephrotoxicity should provide insights into other heavy metal (e.g. Pb(2+), Hg(2+)) nephropathies and various forms of acquired Fanconi syndrome.
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PMID:Nephrotoxicity and the proximal tubule. Insights from cadmium. 1275 69

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