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中华肾病研究电子杂志

中华肾病研究电子杂志 ›› 2024, Vol. 13 ›› Issue (01) : 16 -25. doi: 10.3877/cma.j.issn.2095-3216.2024.01.003

论著

富亮氨酸α-2糖蛋白1增强间充质干细胞对急性肾损伤的疗效研究
张益帆1, 耿晓东2, 冀雨薇1, 张可颖1, 林淑芃2, 蔡广研2, 陈香美2, 洪权2,†()   
  1. 1. 100853　北京，中国人民解放军总医院第一医学中心肾脏病医学部、肾脏疾病全国重点实验室、国家慢性肾病临床医学研究中心、肾脏疾病研究北京市重点实验室；100853　北京，解放军医学院
    2. 100853　北京，中国人民解放军总医院第一医学中心肾脏病医学部、肾脏疾病全国重点实验室、国家慢性肾病临床医学研究中心、肾脏疾病研究北京市重点实验室
  • 收稿日期:2023-08-29 出版日期:2024-02-28
  • 通信作者: 洪权
  • 基金资助:
    国家重点研发计划项目(2018YFE0126600); 国家自然科学基金项目(82270758，82070741，82204744，82030025); 三亚市医疗卫生科技创新项目(2014YW33)

LRG1 enhanced the efficacy of mesenchymal stem cells in the treatment of acute kidney injury

Yifan Zhang1, Xiaodong Geng2, Yuwei Ji1, Keying Zhang1, Shupeng Lin2, Guangyan Cai2, Xiangmei Chen2, Quan Hong2,†()   

  1. 1. Department of Nephrology, First Medical Center of Chinese PLA General Hospital, National Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing 100853, China; Chinese PLA Medical School, Beijing 100853, China
    2. Department of Nephrology, First Medical Center of Chinese PLA General Hospital, National Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing 100853, China
  • Received:2023-08-29 Published:2024-02-28
  • Corresponding author: Quan Hong
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引用本文：

张益帆, 耿晓东, 冀雨薇, 张可颖, 林淑芃, 蔡广研, 陈香美, 洪权. 富亮氨酸α-2糖蛋白1增强间充质干细胞对急性肾损伤的疗效研究[J/OL]. 中华肾病研究电子杂志, 2024, 13(01): 16-25.

Yifan Zhang, Xiaodong Geng, Yuwei Ji, Keying Zhang, Shupeng Lin, Guangyan Cai, Xiangmei Chen, Quan Hong. LRG1 enhanced the efficacy of mesenchymal stem cells in the treatment of acute kidney injury[J/OL]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2024, 13(01): 16-25.

目的

探究富亮氨酸α-2糖蛋白1(LRG1)预处理间充质干细胞(MSCs)对急性肾损伤(AKI)疗效的影响。

方法

8周龄雄性C57BL/6小鼠随机分为4组：假手术组(Sham组)、缺血再灌注损伤组(IRI组)、MSCs组和LRG1-MSCs组。采用左侧肾蒂夹闭30 min，右侧肾切除的方法构建肾单侧IRI模型。Sham组不予治疗，IRI组尾静脉注射等体积磷酸盐缓冲液(PBS)，MSCs组尾静脉注射MSCs，LRG1-MSCs组尾静脉注射LRG1预处理的MSCs。术后3 d检测各组小鼠的血清肌酐(Scr)、血尿素氮(BUN)水平。肾脏病理PAS染色后，通过急性肾小管坏死(ATN)评分评估肾损伤情况。Western印迹检测肾组织肾损伤分子-1(KIM-1)蛋白的表达水平。体外实验，将人近端肾小管上皮细胞(HK-2 cells)分为4组：对照组(Control组，正常HK-2细胞)、缺氧/复氧组(H/R组，H/R诱导的HK-2细胞)、MSCs组(H/R诱导的HK-2细胞与MSCs共培养)和LRG1-MSCs组(H/R诱导的HK-2细胞与LRG1-MSCs共培养)。Western印迹检测HK-2细胞凋亡相关蛋白(Bax、Bcl-2)和炎症相关蛋白(TNF-α、IL-6)的表达水平。采用细胞计数试剂盒检测LRG1对MSCs活力影响。细胞划痕实验检测LRG1对MSCs迁移能力的影响。RNA测序探究LRG1预处理MSCs对肾损伤修复影响的作用机制。酶联免疫吸附测定检测LRG1-MSCs培养上清中的前列腺素E2(PGE2)含量。

结果

IRI组小鼠的Scr、BUN、ATN评分和KIM-1表达水平均明显高于Sham组(P均<0.05)；MSCs组和LRG1-MSCs组小鼠的Scr、BUN、ATN评分和KIM-1表达水平均明显低于IRI组(P均<0.05)；LRG1-MSCs组小鼠的Scr、BUN、ATN评分和KIM-1表达水平均明显低于MSCs组(P均<0.05)。体外实验结果显示，MSCs组和LRG1-MSCs组HK-2细胞的Bax、IL-6和TNF-α蛋白表达均明显低于H/R组，而Bcl-2蛋白表达高于H/R组(P均<0.05)；LRG1-MSCs组HK-2细胞的Bax、IL-6和TNF-α蛋白表达均明显低于MSCs组，而Bcl-2蛋白表达高于MSCs组(P均<0.05)。250 ng/ml LRG1处理24 h能够明显促进MSCs增殖和迁移(P均<0.05)。RNA测序显示，LRG1预处理MSCs后前列腺素内过氧化物合酶2(PTGS2)基因表达上调，LRG1-MSCs培养上清液中PGE2含量明显增高(P均<0.05)。

结论

LRG1能够促进MSCs分泌PGE2，减轻凋亡和炎症反应，增强了MSCs对AKI的疗效。

关键词: 富亮氨酸α-2糖蛋白1, 间充质干细胞, 急性肾损伤
Objective

To investigate the impact of leucine-rich α-2-glycoprotein 1 (LRG1) pretreatment of mesenchymal stem cells (MSCs) on the efficacy of MSCs in the treatment of acute kidney injury (AKI).

Methods

Eight-week-old male C57BL/6 mice were randomly divided into four groups: sham operation group (sham group), ischemia/reperfusion injury (IRI) group, MSCs group, and LRG1-MSCs group. The renal IRI mouse model was established by clamping of the left renal pedicle for 30 min and nephrectomy of the right kidney. The sham group did not receive any treatment, while the IRI group, MSCs group, and LRG1-MSCs group were injected through the tail vein with the same volume of phosphate buffer saline (PBS), MSCs, and LRG1-pretreated MSCs, respectively. These mice were sacrificed at 3 d after surgery, and the serum creatinine (Scr) and blood urea nitrogen (BUN) levels were measured. Renal pathological injury was evaluated by acute tubular necrosis (ATN) score after periodic acid-Schiff (PAS) staining. The protein expression of kidney injury molecule-1 (KIM-1) was detected by Western blot in kidney tissues. For the in vitro experiments, HK-2 cells were divided into four groups: control group (normal HK-2 cells), hypoxia/reoxygenation group (HK-2 cells with treatment of hypoxia/reoxygenation), MSCs group (hypoxia/reoxygenation-treated HK-2 cells co-cultured with MSCs), and LRG1-MSCs group (hypoxia/reoxygenation-treated HK-2 cells co-cultured with LRG1-pretreated MSCs). Western blot analysis was used to detect the expression levels of apoptosis-related proteins (Bax and Bcl-2) and inflammation-related proteins (TNF-α and IL-6) in HK-2 cells. Cell proliferation was assessed by the cell counting kit-8 (CCK-8) method. The effect of LRG1 on the migration of MSCs was analyzed by the wound healing assay. To explore the mechanism by which LRG1 enhanced the therapeutic effect of MSCs in IRI mice, RNA sequencing was performed. The content of prostaglandin E2 (PGE2) in the supernatant of cells was detected by enzyme linked immunosorbent assay (ELISA).

Results

The levels of Scr, BUN, ATN score, and KIM-1 expression were significantly higher in the IRI group than in the sham group (all P<0.05). In contrast, the Scr, BUN, ATN score, and KIM-1 expression levels in both the MSCs group and LRG1-MSCs group were all significantly lower than those in the IRI group (all P<0.05). Furthermore, the LRG1-MSCs group exhibited significantly lower levels of Scr, BUN, ATN score, and KIM-1 expression than the MSCs group (all P<0.05). In vitro experiments revealed that the protein levels of Bax, IL-6, and TNF-α of both the MSCs group and LRG1-MSCs group were significantly lower than those in the H/R group, while Bcl-2 protein level was higher than that in the H/R group (all P<0.05). Additionally, the expression levels of Bax, TNF-α, and IL-6 proteins in HK-2 cells of the LRG1-MSCs group were lower than those in the MSCs group, while the expression level of Bcl-2 protein was higher than that in the MSCs group. Pretreatment with 250 ng/ml of LRG1 for 24 h significantly promoted the proliferation and migration of MSCs (both P<0.05). RNA sequencing revealed upregulation of the prostaglandin-endoperoxide synthase 2 (PTGS2) gene expression in LRG1-pretreated MSCs, and significant increase of PGE2 content in the culture supernatant of LRG1-MSCs group (both P<0.05).

Conclusion

LRG1 may promote the secretion of PGE2 by MSCs, reduce apoptosis and inflammatory response, and enhance the efficacy of MSCs in the treatment of AKI.

Key words: Leucine-rich α-2-glycoprotein 1, Mesenchymal stem cells, Acute kidney injury
图1 各组小鼠血清肌酐和血尿素氮水平注：A：各组血清肌酐水平；B：各组血尿素氮水平；与Sham组相比，aP<0.05；与IRI组相比，bP<0.05；与MSCs组相比，cP<0.05
图2 各组小鼠肾组织PAS染色及急性肾小管坏死评分注：A：各组肾组织病理PAS染色，比例尺＝50 μm；B：各组急性肾小管坏死评分比较；与Sham组相比，aP<0.05；与IRI组相比，bP<0.05；与MSCs组相比，cP<0.05
图3 Western印迹检测各组肾损伤分子-1表达水平及半定量分析注：KIM-1：肾损伤分子-1；β-tubulin：β-微管蛋白；与Sham组相比，aP<0.05;与IRI组相比，bP<0.05；与MSCs组相比，cP<0.05
图4 Western印迹检测各组凋亡和炎症相关蛋白表达水平及半定量分析注：Bcl-2：B细胞淋巴瘤/白血病-2；Bax：B细胞淋巴瘤/白血病-2相关X蛋白；TNF-α：肿瘤坏死因子-α；IL-6：白介素-6；GAPDH：甘油醛-3-磷酸脱氢酶；与Sham组相比，aP<0.05；与H/R组相比，bP<0.05；与MSCs组相比，cP<0.05
图5 富亮氨酸α-2糖蛋白1对间充质干细胞存活率的影响注：A：CCK-8法检测富亮氨酸α-2糖蛋白1(LRG1)不同处理浓度和时间对间充质干细胞(MSCs)存活率影响的折线图；B：CCK-8法检测LRG1不同处理浓度和时间对MSCs存活率影响的柱状图；不同处理时间MSCs存活率的比较，MSCs预处理24 h的存活率与预处理48 h相比，aP<0.05；MSCs预处理24 h的存活率与预处理72 h相比，bP<0.05；MSCs预处理48 h的存活率与预处理72 h相比，cP<0.05
图6 富亮氨酸α-2糖蛋白1对间充质干细胞迁移的影响注：富亮氨酸α-2糖蛋白1(LRG1)预处理间充质干细胞(MSCs)组与未处理组细胞迁移情况，比例尺＝200 μm；LRG1预处理MSCs 12 h与未处理组相比，aP<0.05；LRG1预处理MSCs 24 h与未处理组相比，bP<0.05；LRG1预处理MSCs 24 h与预处理12 h相比，cP<0.05
图7 富亮氨酸α-2糖蛋白1处理组与未处理组差异表达基因注：A：富亮氨酸α-2糖蛋白1(LRG1)处理组与未处理组差异表达基因(DEGs)数目B：DEGs火山图，红色代表上调的DEGs;蓝色代表下调的DEGs;灰色代表非DEGs；C和D：GO富集分析和KEGG富集分析；气泡的大小表示注释到某个通路上的基因数目，颜色代表富集的显著性
图8 富亮氨酸α-2糖蛋白1预处理间充质干细胞促进前列腺素E2分泌注：富亮氨酸α-2糖蛋白1(LRG1)处理间充质干细胞(MSCs) 12 h、24 h后，检测细胞上清液中前列腺素E2(PGE2)含量，LRG1预处理MSCs 12 h与未处理组相比，aP<0.05；LRG1预处理MSCs 24 h与未处理组相比，bP<0.05；LRG1预处理MSCs 24 h与预处理12 h相比，cP<0.05
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