Potential Role for the Nuclear Transcription Factor NF-κB in the Pathogenesis of Ureteropelvic Junction Obstruction

Abstract

Background and Purpose

: In an effort to better understand the pathophysiology of ureteropelvic junction (UPJ) obstruction and to determine possible predisposing factors for endopyelotomy failures, we compared the activation of the nuclear factor NF-κB and proinflammatory cytokines in patients who failed endopyelotomy and post-primary pyeloplasty patients. We hypothesized that an imbalance toward proinflammatory cytokines may promote fibrosis prior to and after endopyelotomy in patients with severe hydronephrosis.

Patients and Methods

: The charts of patients who underwent open pyeloplasty at our institution were reviewed. Group I was the control group, consisting of 10 patients who had undergone radical nephrectomy for renal-cell carcinoma without involvement of the renal pelvis. Group II was the endopyelotomy failure group and included 11 patients over the age of 15 years treated for symptomatic UPJ obstruction. Group III included six patients who underwent primary pyeloplasty. Paraffin-embedded blocks of UPJ segments from each of these patients were obtained, and immunohistochemical detection of NF-κB activation, interleukin (IL)-6, and hypoxia-inducing factor (HIF) was performed. As an in-vitro model, activation of NF-κB and cytokine gene expression were also monitored in human bladder T24 urothelial cells 24 hours after exposure to hypoxia (1% O₂) in the presence and absence of NF-κB inhibitor. The activation of NF-κB was determined by immunocytochemical analysis, whereas cytokine gene expression was measured using reverse transcriptase-polymerase chain reaction.

Results

: Immunoreactivity to NF-κB was observed in the nuclei of the urothelium and muscle layer in all patients in group II. Such immunostaining suggests increased nuclear translocation and activation of this transcription factor. Those patients with increased expression of NF-κB demonstrated increases in IL-6 expression as well. Hypoxia-inducing factor was identified in all the tissue samples tested in group II. Stimulation of the human urothelial cells by hypoxia, known to activate NF-κB, resulted in an increase in the levels of IL-1 and IL-6 transcripts compared with hypoxia-exposed cells in the presence of NF-κB inhibitors.

Conclusions

: The NF-κB factor was upregulated and proinflammatory cytokines were activated in patients with UPJ obstruction who failed endopyelotomy. Proinflammatory cytokines upregulated by this nuclear factor can result in fibrosis and affect healing after endopyelotomy. Hypoxia appears to activate this nuclear factor. Further studies correlating the degree of hydronephrosis with the activation of HIF are necessary to clarify the role of severe hydronephrosis and its management in UPJ obstruction.