Proximal tubular efflux transporters involved in renal excretion of p-cresyl sulfate and p-cresyl glucuronide: Implications for chronic kidney disease pathophysiology.
Toxicol In Vitro
; 29(7): 1868-77, 2015 Oct.
Article
en En
| MEDLINE
| ID: mdl-26216510
ABSTRACT
The uremic solutes p-cresyl sulfate (pCS) and p-cresyl glucuronide (pCG) accumulate in patients with chronic kidney disease (CKD), and might contribute to disease progression. Moreover, retention of these solutes may directly be related to renal tubular function. Here, we investigated the role of the efflux transporters Multidrug Resistance Protein 4 (MRP4) and Breast Cancer Resistance Protein (BCRP) in pCS and pCG excretion, and studied the impact of both solutes on the phenotype of human conditionally immortalized renal proximal tubule epithelial cells (ciPTEC). Our results show that p-cresol metabolites accumulate during CKD, with a shift from sulfation to glucuronidation upon progression. Moreover, pCS inhibited the activity of MRP4 by 40% and BCRP by 25%, whereas pCG only reduced MRP4 activity by 75%. Moreover, BCRP-mediated transport of both solutes was demonstrated. Exposure of ciPTEC to pCG caused epithelial-to-mesenchymal transition, indicated by increased expression of vimentin and Bcl-2, and diminished E-cadherin. This was associated with altered expression of key tubular transporters. In conclusion, BCRP is likely involved in the renal excretion of both solutes, and pCG promotes phenotypical changes in ciPTEC, supporting the notion that uremic toxins may be involved in CKD progression by negatively affecting renal tubule cell phenotype and functionality.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Ésteres del Ácido Sulfúrico
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Transportadoras de Casetes de Unión a ATP
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Cresoles
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Glucurónidos
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Proteínas Asociadas a Resistencia a Múltiples Medicamentos
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Túbulos Renales Proximales
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Proteínas de Neoplasias
Límite:
Adult
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Aged
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Toxicol In Vitro
Asunto de la revista:
TOXICOLOGIA
Año:
2015
Tipo del documento:
Article