Relationship of clusterin with renal inflammation and fibrosis after the recovery phase of ischemia-reperfusion injury.
Relationship of clusterin with renal inflammation and fibrosis after the recovery phase of ischemia-reperfusion injury.
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DOI：
10.1186/s12882-016-0348-x
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发表时间：
2016-09-20
期刊：
影响因子：
2.3
通讯作者：
Du C
中科院分区：
文献类型：
--
作者：
Guo J;Guan Q;Liu X;Wang H;Gleave ME;Nguan CY;Du C
急性肾损伤(AKI)后的长期结果包括逐渐丧失功能和进展为慢性肾脏疾病(CKD)；然而，AKI发展为CKD的发病机制仍很大程度上尚不清楚。聚集素(CLU)是一种伴侣样蛋白，可减轻肾脏缺血再灌注损伤(IRI)，促进肾脏IRI后的组织修复。本研究探讨了CLU在IRI向肾纤维化转化过程中的作用。在32℃体温下夹闭肾蒂28分钟，诱导野生型(WT)C57BL/6J(B6)与CLU基因敲除(KO)B6小鼠左肾IRI，组织学观察组织损伤，流式细胞仪分析组织学改变，聚合酶链式反应(PCR)芯片检测纤维化相关基因表达。肾脏重量减轻可由IRI引起，但不受CLU-KO的影响。WT和KO肾功能相似，再灌流14d时细胞浸润和纤维化程度最低。30天后，KO组小鼠肾功能受损程度明显大于WT组，表现为血肌酐和BUN水平升高，肾小管上皮细胞浸润增多(CD8细胞和巨噬细胞)，肾小管损伤加重，组织纤维化(肾小球病变、间质纤维化和血管纤维化)加重。聚合酶链式反应显示CLU缺乏与肾脏CCL12、COL3a1、MMP9和TIMP1表达上调及EGF表达下调有关。我们的数据表明，CLU缺乏加重了肾脏IRI后的肾脏炎症和组织纤维化，这可能是通过多条途径介导的。本文的在线版本(doi：10.1186/s12882-0160348-x)包含补充材料，授权用户可以使用。
Long-term outcomes after acute kidney injury (AKI) include incremental loss of function and progression towards chronic kidney disease (CKD); however, the pathogenesis of AKI to CKD remains largely unknown. Clusterin (CLU) is a chaperone-like protein that reduces ischemia-reperfusion injury (IRI) and enhances tissue repair after IRI in the kidney. This study investigated the role of CLU in the transition of IRI to renal fibrosis. IRI was induced in the left kidneys of wild type (WT) C57BL/6J (B6) versus CLU knockout (KO) B6 mice by clamping the renal pedicles for 28 min at the body temperature of 32 °C. Tissue damage was examined by histology, infiltrate phenotypes by flow cytometry analysis, and fibrosis-related gene expression by PCR array. Reduction of kidney weight was induced by IRI, but was not affected by CLU KO. Both WT and KO kidneys had similar function with minimal cellular infiltration and fibrosis at day 14 of reperfusion. After 30 days, KO kidneys had greater loss in function than WT, indicated by the higher levels of both serum creatinine and BUN in KO mice, and exhibited more cellular infiltration (CD8 cells and macrophages), more tubular damage and more severe tissue fibrosis (glomerulopathy, interstitial fibrosis and vascular fibrosis). PCR array showed the association of CLU deficiency with up-regulation of CCL12, Col3a1, MMP9 and TIMP1 and down-regulation of EGF in these kidneys. Our data suggest that CLU deficiency worsens renal inflammation and tissue fibrosis after IRI in the kidney, which may be mediated through multiple pathways. The online version of this article (doi:10.1186/s12882-016-0348-x) contains supplementary material, which is available to authorized users.
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