Leukemia inhibitory factor is a therapeutic target for renal interstitial fibrosis.
Leukemia inhibitory factor is a therapeutic target for renal interstitial fibrosis.
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白血病抑制因子是肾间质纤维化的治疗靶点
DOI：
10.1016/j.ebiom.2022.104312
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发表时间：
2022-12
期刊：
影响因子：
11.1
通讯作者：
Nie, Jing
中科院分区：
文献类型：
--
作者：
Xu, Shihui;Yang, Xiaobing;Chen, Qingzhou;Liu, Zhuoliang;Chen, Ying;Yao, Xiaotian;Xiao, An;Tian, Jianwei;Xie, Liling;Zhou, Miaomiao;Hu, Zheng;Zhu, Fengxin;Xu, Xin;Hou, Fanfan;Nie, Jing
IL6 家族成员在器官纤维化（包括肾间质纤维化 (TIF)）中的作用已被广泛探索。然而，很少有研究在同一组患者中同时检查它们。此外，白血病抑制因子（LIF）在TIF中的作用仍不清楚。公共数据库和我们的检测中慢性肾病 (CKD) 患者肾活检的 RNA-seq 数据用于分析 IL6 家族成员的转录水平。采用两种 TIF 小鼠模型（单侧输尿管梗阻 (UUO) 和缺血再灌注损伤 (IRI)）来验证这一发现。为了评估 LIF 在体内的作用，使用短发夹 RNA、lenti-GFP-LIF 分别敲低 LIF 受体 (LIFR) 和过表达 LIF。 LIF 中和抗体用于治疗研究。在前瞻性观察患者队列中研究了尿 LIF 是否可以作为 CKD 进展的有希望的预测因子。在 IL6 家族成员中，LIF 是人和小鼠肾纤维化病变中表达最上调的一种。 LIF 的 mRNA 水平与 eGFR 呈负相关，相关性最强，P 值最小。通过 Kaplan-Meier 分析，CKD 患者的 LIF 基线尿浓度可预测 CKD 进展为终末期肾病的风险。在小鼠 TIF 模型中，LIFR 的敲低可减轻 TIF；相反，过度表达 LIF 会加剧 TIF。最令人鼓舞的是，通过给小鼠施用 LIF 中和抗体，观察到了针对 TIF 的明显功效。从机制上讲，LIF-LIFR-EGR1 轴和 Sonic Hedgehog 信号在成纤维细胞和近端肾小管细胞之间形成恶性循环，从而增强 LIF 表达并通过 ERK 和 STAT3 激活促进促纤维化反应。这项研究发现，LIF 是 CKD 进展的非侵入性生物标志物，也是 TIF 的潜在治疗靶点。在手稿的致谢部分中有说明。
The role of the IL6 family members in organ fibrosis, including renal interstitial fibrosis (TIF), has been widely explored. However, few studies have ever simultaneously examined them in the same cohort of patients. Besides, the role of leukemia inhibitory factor (LIF) in TIF remains unclear. RNA-seq data of kidney biopsies from chronic kidney disease (CKD) patients, in both public databases and our assays, were used to analyze transcript levels of IL6 family members. Two TIF mouse models, the unilateral ureteral obstruction (UUO) and the ischemia reperfusion injury (IRI), were employed to validate the finding. To assess the role of LIF in vivo, short hairpin RNA, lenti-GFP-LIF was used to knockdown LIF receptor (LIFR), overexpress LIF, respectively. LIF-neutralizing antibody was used in therapeutic studies. Whether urinary LIF could be used as a promising predictor for CKD progression was investigated in a prospective observation patient cohort. Among IL6 family members, LIF is the most upregulated one in both human and mouse renal fibrotic lesions. The mRNA level of LIF negatively correlated with eGFR with the strongest correlation and the smallest P value. Baseline urinary concentrations of LIF in CKD patients predict the risk of CKD progression to end-stage kidney disease by Kaplan–Meier analysis. In mouse TIF models, knockdown of LIFR alleviated TIF; conversely, overexpressing LIF exacerbated TIF. Most encouragingly, visible efficacy against TIF was observed by administering LIF-neutralizing antibodies to mice. Mechanistically, LIF–LIFR-EGR1 axis and Sonic Hedgehog signaling formed a vicious cycle between fibroblasts and proximal tubular cells to augment LIF expression and promote the pro-fibrotic response via ERK and STAT3 activation. This study discovered that LIF is a noninvasive biomarker for the progression of CKD and a potential therapeutic target of TIF. Stated in the Acknowledgements section of the manuscript.
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影响因子：
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作者：
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DOI：
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发表时间：
2001-05-01
影响因子：
5.5
作者：
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