IL-33/ST2 axis mediates hyperplasia of intrarenal urothelium in obstructive renal injury.
IL-33/ST2 axis mediates hyperplasia of intrarenal urothelium in obstructive renal injury.
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DOI：
10.1038/s12276-018-0047-8
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发表时间：
2018-04-20
影响因子：
12.8
通讯作者：
Chang YJ
中科院分区：
文献类型：
--
作者：
Chen WY;Yang JL;Wu YH;Li LC;Li RF;Chang YT;Dai LH;Wang WC;Chang YJ
单层肾内尿路上皮覆盖肾乳头和肾盂输尿管连接处（UPJ）。为了应对梗阻或缺血性损伤期间肾压升高，肾内尿路上皮细胞开始增殖并形成多层尿路上皮。关于肾梗阻期间尿路上皮增生的机制和病理生理学作用知之甚少。在这项研究中，我们研究了单侧输尿管梗阻 (UUO) 引起的梗阻性损伤的肾脏中白细胞介素 (IL)-33（一种 IL-1 家族细胞因子）的表达。 UUO 后 2 天，肾积水尿液和血清中 IL-33 水平上调。 UUO 肾脏中表达 ST2 的免疫细胞数量增加。我们发现皮质层、髓质层以及 UPJ 基质的波形蛋白阳性细胞中 IL-33 表达上调。此外，IL-33 表达主要在 UPJ 的多层角蛋白 5 阳性尿路上皮细胞中诱导。在表达尿斑蛋白 3a 的终末分化浅表伞细胞中未检测到 IL-33。在体内，我们证实 IL33 或其受体 ST2 的缺乏会减弱 UUO 诱导的 UPJ 尿路上皮的增生。 IL33 缺乏会减弱 UUO 诱导的 2 型炎症细胞因子的表达，并上调 UPJ 组织中的尿斑蛋白和尿路上皮分化信号传导。我们的结果总体表明，IL-33/ST2 轴介导先天免疫反应的激活，并通过调节梗阻性肾损伤中的尿路上皮分化来促进尿路上皮增生。炎症信号蛋白可能在与尿路阻塞相关的肾脏损伤中发挥重要作用。未经治疗的梗阻性肾病可导致肾损伤，尤其是年轻患者。由高雄长庚纪念医院的陈伟宇和台北中央研究院的张亚仁领导的台湾研究人员，重点研究了一条显然与这种疾病的病理学有关的信号通路。研究人员利用手术诱发的梗阻性肾病动物模型，观察到受伤后免疫激活蛋白白细胞介素 (IL)-33 的产生量激增。这种蛋白质随后激活多种免疫细胞类型，并刺激尿道上皮细胞亚群的异常生长。这种过度生长可能会直接导致随后的肾脏损伤和功能障碍，尽管需要更多的研究来证实这一点。
The monolayered intrarenal urothelium covers the renal papilla and ureteropelvic junction (UPJ). In response to increased renal pressure during obstruction or ischemic injuries, intrarenal urothelial cells begin to proliferate and form a multilayered urothelium. Little is known regarding the mechanism and pathophysiological role of urothelium hyperplasia during renal obstruction. In this study, we investigated the expression of interleukin (IL)-33, an IL-1 family cytokine, in kidneys with unilateral ureteral obstruction (UUO)-induced obstructive injury. IL-33 levels in hydronephrotic urine and serum were upregulated 2 days after UUO. The number of ST2-expressing immune cells was increased in the UUO kidney. We found that IL-33 was upregulated in vimentin-positive cells in the cortical and medullar layers and the UPJ stroma. Moreover, IL-33 expression was predominantly induced in multilayered keratin 5-positive urothelial cells in the UPJ. IL-33 was not detected in terminally differentiated superficial umbrella cells expressing uroplakin 3a. In vivo, we confirmed that deficiency of IL33 or its receptor ST2 attenuated UUO-induced hyperplasia of the UPJ urothelium. Deficiency of IL33 attenuated the expression of UUO-induced type 2 inflammatory cytokines and upregulated uroplakins and urothelial differentiation signaling in UPJ tissues. Our results collectively suggest that the IL-33/ST2 axis mediates the activation of innate immune responses and contributes to urothelial hyperplasia by regulating urothelial differentiation in obstructive kidney injury. An inflammatory signaling protein may play an important role in kidney damage associated with urinary tract blockage. Untreated obstructive nephropathy can lead to kidney injury, particularly in younger patients. Taiwanese researchers led by Wei-Yu Chen at the Kaohsiung Chang Gung Memorial Hospital and Ya-Jen Chang at the Academia Sinica, Taipei, homed in on a signaling pathway that apparently contributes to the pathology of this condition. Using an animal model of surgically induced obstructive nephropathy, the researchers observed a post-injury spike in production of an immunity-activating protein called interleukin (IL)-33. This protein subsequently activates a host of immune cell types, and also stimulates abnormal growth in a subset of urinary tract epithelial cells. This excessive growth may directly contribute to subsequent damage and functional impairment of the kidney, although more research will be needed to confirm this.
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影响因子：
19.6
作者：
Chiou, YY;Shieh, CC;Tang, MJ
通讯作者：
Tang, MJ
DOI：
10.1016/j.jaci.2011.10.036
发表时间：
2012-01
期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
Kim HY;Chang YJ;Subramanian S;Lee HH;Albacker LA;Matangkasombut P;Savage PB;McKenzie AN;Smith DE;Rottman JB;DeKruyff RH;Umetsu DT
通讯作者：
Umetsu DT
DOI：
10.1038/jid.2015.406
发表时间：
2016-02
期刊：
The Journal of investigative dermatology
影响因子：
--
作者：
Rak GD;Osborne LC;Siracusa MC;Kim BS;Wang K;Bayat A;Artis D;Volk SW
通讯作者：
Volk SW
影响因子：
9.1
作者：
Bao, Yu-Shi;Na, Shi-Ping;Xie, Ru-Juan
通讯作者：
Xie, Ru-Juan
DOI：
10.1073/pnas.1424236112
发表时间：
2015-06-09
影响因子：
11.1
作者：
Chen, Wei-Yu;Hong, Jaewoo;Lee, Richard T.
通讯作者：
Lee, Richard T.