Interleukin-10 deficiency aggravates kidney inflammation and fibrosis in the unilateral ureteral obstruction mouse model
Interleukin-10 deficiency aggravates kidney inflammation and fibrosis in the unilateral ureteral obstruction mouse model
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白细胞介素10缺乏会加重单侧输尿管梗阻小鼠模型的肾脏炎症和纤维化
DOI：
10.1038/labinvest.2013.64
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发表时间：
2013-07-01
影响因子：
5
通讯作者：
Chen, Nan
中科院分区：
文献类型：
--
作者：
Jin, Yuanmeng;Liu, Ruijie;Chen, Nan
白细胞介素-10作为一种通用的免疫抑制细胞因子，也通过复杂的机制负调控炎症反应。最近的研究表明，IL-10也可能抑制各种病变模型的纤维化。然而，IL-10在肾纤维化中的作用尚未得到证实。在这里，我们通过在IL-10敲除（−/−）小鼠中建立单侧输尿管梗阻（UUO）模型来研究IL-10在肾小管间质纤维化发展中的作用。我们对8周龄IL-10 - / -雄性小鼠和年龄和性别匹配的野生型仔鼠进行了假性或单侧输尿管梗阻手术。在术后7天或14天处死小鼠，取肾组织进行RNA、蛋白质和免疫组织化学分析。我们的研究结果发现，IL-10缺乏导致肾纤维化增强，表现为更严重的肾小管损伤和胶原沉积，以及促纤维化基因（包括α-SMA、MMP-2、纤维连接蛋白、FSP-1和vimentin）的表达增加。我们的研究结果还发现，IL-10−/−UUO小鼠出现了更严重的肾脏炎症，炎症细胞浸润显著增加，炎症趋化因子（MCP-1和RANTES）和细胞因子（TNF-α, IL-6， IL-8和M-CSF）上调。进一步研究发现，肾脏炎症和纤维化的增强与TGF-β/Smad3和NF-κB信号通路的激活显著增加有关。总之，我们的研究提供了直接证据，证明IL-10是一种内源性细胞因子，在防止肾脏炎症和纤维化的发展中起关键作用。增强IL-10的表达可能是一种潜在的抗纤维化治疗慢性肾脏疾病的方法。
Interleukin-10 functions as a general immunosuppressive cytokine, which also negatively regulates inflammatory responses through complex mechanisms. Recent studies suggested that IL-10 may also inhibit fibrosis in various diseased models. However, the role of IL-10 in renal fibrosis has not been demonstrated. Here, we investigated the effects of IL-10 in the development of renal tubulointerstitial fibrosis by creating the unilateral ureteral obstruction (UUO) model in IL-10 knockout (−/−) mice. We performed sham or unilateral ureteral obstruction surgery in 8-week-old IL-10−/− male mice and age and sex-matched wild type littermates. Mice were killed at 7 days or 14 days post surgery and renal tissues were obtained for RNA, protein, and immunohistochemical analysis. Our results found IL-10 deficiency resulted in enhanced renal fibrosis demonstrated by more severe tubular injury and collagen deposition and higher expression of pro-fibrotic genes (including α-SMA, MMP-2, fibronectin, FSP-1 and vimentin). Our results also found IL-10−/− UUO mice developed more severe renal inflammation with a significant increase in inflammatory cells infiltration, and upregulation of inflammatory chemokines (MCP-1 and RANTES), and cytokines (TNF-α, IL-6, IL-8, and M-CSF). Further study revealed that enhanced renal inflammation and fibrosis was associated with significantly increased activation of both TGF-β/Smad3 and NF-κB signaling pathways. In summary, our study provides the direct evidence that IL-10 is an endogenous cytokine that has a key role in protecting against development of renal inflammation and fibrosis. Enhancement of IL-10 expression could be a potential anti-fibrosis therapy for patients with chronic kidney diseases.