Urothelial differentiation in chronically urine-deprived bladders of patients with end-stage renal disease

Abstract

Background. It is unknown whether normal bladder voiding function, or soluble factors present in urine, contribute to the maturation and maintenance of the differentiated state of the uroepithelial cell lining of the lower urinary tract. Methods. We used the urothelium of anuric patients on long-term hemodialysis, sampled at the time of renal transplantation, to investigate the expression of urothelial differentiation-associated antigens, including uroplakins (UPIa, UPIb, UPII, and UPIIIa), cytokeratin isotypes (CK7, CK8, CK13, CK14, CK17, CK18, and CK20), nuclear hormone receptors [peroxisome proliferators activated receptor-γ (PPAR-γ) and retinoid X receptor-α (RXR-α)], and a cell cycle marker (Ki-67). To determine whether urinary metabolites of the arachidonic pathway could induce urothelial differentiation, cultured normal human urothelial (NHU) cells were treated with 15-deoxy-Δ12, 14-prostaglandin J2 (15d-PGJ2) and prostaglandin J2 (PGJ2). The expression levels of the markers of differentiation, the uroplakins, were assessed by ribonuclease protection assay. Results. When compared in a blinded analysis against control normal urothelium, no significant changes were found in the expression or localization patterns of any of the antigens studied in the anuric patients. Furthermore, neither 15d-PGJ2 nor PGJ2 were able to induce expression of the UPII gene in NHU cells, in contrast to cultures exposed to the pharmacologic PPAR-γ agonist, troglitazone. Conclusion. These data provide prima facie evidence that exogenous urine-derived factors do not modulate the differentiation program in urothelium, suggesting that other urothelial- or serum-derived factors are likely to be involved. These findings are important in understanding postdevelopmental maturation and functional relationships in urologic tissues of the adult organism. © 2005 by the International Society of Nephrology.