Potential role for the nuclear transcription factor NF-κB in the pathogenesis of ureteropelvic junction obstruction
Potential role for the nuclear transcription factor NF-κB in the pathogenesis of ureteropelvic junction obstruction
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DOI：
10.1089/089277902320913323
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发表时间：
2002-10-01
影响因子：
2.7
通讯作者：
Abdel-Mageed, AB
中科院分区：
文献类型：
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作者：
Ruiz-Deya, G;Sikka, SC;Abdel-Mageed, AB
背景和目的：为了更好地了解肾盂输尿管连接处（UPJ）阻塞的病理生理机制，并确定肾盂内切开术失败的可能易感因素，我们比较了肾盂内切开术失败患者和原发性肾盂成形术后患者核因子NF-kappaB和促炎细胞因子的激活情况。我们假设，促炎细胞因子的失衡可能会促进严重肾积水患者在脊髓切开术前后的纤维化。患者与方法：回顾我院开腹肾盂成形术患者的病历。第一组为对照组，包括10例因肾细胞癌行根治性肾切除术而未累及肾盂的患者。第11组为肾盂内切开术失败组，包括11例15岁以上因症状性UPJ梗阻治疗的患者。第三组包括6例接受原发性肾盂成形术的患者。从这些患者中分别获得UPJ片段石蜡包埋块，并进行NF-kappaB活化、白细胞介素(IL)-6和缺氧诱导因子（HIF）的免疫组化检测。作为体外模型，在存在和不存在NF-kappaB抑制剂的情况下，在缺氧（1% O-2）暴露24小时后，还监测了人膀胱T24尿路上皮细胞NF-kappaB的激活和细胞因子基因表达。NF-kappaB的激活通过免疫细胞化学分析确定，而细胞因子基因表达通过逆转录-聚合酶链反应测定。结果：II组患者尿路上皮细胞核及肌层对NF-kappaB均有免疫反应。这种免疫染色表明该转录因子的核易位和活化增加。NF-kappaB表达增加的患者IL-6表达也增加。II组所有组织样本均存在缺氧诱导因子。缺氧对人尿路上皮细胞的刺激，已知会激活NF-kappaB，与NF-kappaB抑制剂存在下的缺氧暴露细胞相比，导致IL-1和IL-6转录物水平升高。结论：UPJ梗阻性肾盂切开术失败患者NF-kappaB因子上调，促炎因子激活。这种核因子上调的促炎细胞因子可导致纤维化并影响脊髓切开术后的愈合。缺氧似乎激活了这个核因子。为了明确严重肾积水及其处理在UPJ梗阻中的作用，有必要进一步研究肾积水程度与HIF激活之间的关系。
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-kappaB 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 11 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 inummohistochemical detection of NF-kappaB activation, interleukin (IL)-6, and hypoxia-inducing factor (HIF) was performed. As an in-vitro model, activation of NF-kappaB and cytokine gene expression were also monitored in human bladder T24 urothelial cells 24 hours after exposure to hypoxia (1% O-2) in the presence and absence of NF-kappaB inhibitor. The activation of NF-kappaB was determined by immunocytochemical analysis, whereas cytokine gene expression was measured using reverse transcriptase-polymerase chain reaction.Results: Immunoreactivity to NF-kappaB was observed in the nuclei of the urothelium and muscle layer in all patients in group II. Such inummostaining suggests increased nuclear translocation and activation of this transcription factor. Those patients with increased expression of NF-kappaB 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-kappaB, resulted in an increase in the levels of IL-1 and IL-6 transcripts compared with hypoxia-exposed cells in the presence of NF-kappaB inhibitors.Conclusions: The NF-kappaB 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.