肾损伤分子1介导游离轻链内吞致近端肾小管上皮细胞损伤

doi:10.3969/j.issn.1006-298X.2023.02.004

肾脏病与透析肾移植杂志 ›› 2023, Vol. 32 ›› Issue (2): 121-127.DOI: 10.3969/j.issn.1006-298X.2023.02.004

肾损伤分子1介导游离轻链内吞致近端肾小管上皮细胞损伤

董世惠, 范芸, 夏园园, 杨雪, 刘丰, 杨帆, 梁丹丹, 曾彩虹

出版日期:2023-04-28 发布日期:2023-04-24

Injury of proximal renal tubular epithelial cells induced by kidney injury molecule-1 mediated endocytosis of immunoglobulin free light chain

DONG Shihui, FAN Yun, XIA Yuanyuan, YANG Xue, LIU Feng, YANG Fan, LIANG Dandan, ZENG Caihong

Online:2023-04-28 Published:2023-04-24

摘要/Abstract

摘要： 目的：探究近端肾小管上皮细胞中肾损伤分子1(KIM-1)介导免疫球蛋白轻链(FLCs)内吞对肾小管损伤的影响及机制。
方法：(1)选取4例多发性骨髓瘤肾损伤患者尿标本,采用离子交换层析法纯化FLCs;(2)体外实验构建纯化的FLCs诱导人肾脏近端肾小管上皮细胞(HK-2细胞)损伤模型,继续给予FLCs刺激,并予KIM-1抑制剂TW-37干预;体内实验向小鼠腹腔注射FLCs,14 d后建立FLCs致小鼠肾小管损伤的动物模型,并予TW-37干预。Western Blot检测HK-2细胞和小鼠肾组织KIM-1、megalin、核因子E2相关因子2(Nrf2)、葡萄糖调节蛋白78(GRP78)、α平滑肌肌动蛋白(α-SMA)及转化生长因子β(TGFβ)等水平,ELISA法检测小鼠尿白蛋白/肌酐比值、尿液KIM1的含量,天狼星红染观察小鼠肾间质纤维化程度等。
结果：(1)体外实验中FLCs刺激HK2细胞诱导KIM-1表达增加,并与FLCs存在共定位,TW-37处理后可减少HK-2细胞中FLCs内吞,减轻FLCs刺激所致的肾小管细胞溶酶体的核周聚集,降低氧化应激及纤维化指标表达。(2)动物模型结果显示,TW-37干预可缓解FLCs所致的肾小管损伤,包括尿KIM1水平及肾组织KIM-1表达下降,肾组织氧化应激和纤维化指标表达下降,肾组织胶原沉积减轻。
结论：KIM-1可介导肾近端小管细胞内吞FLCs,抑制KIM-1有助于缓解FLCs造成的肾损伤。

关键词: 肾小管上皮细胞, 免疫球蛋白游离轻链, 肾脏损伤分子1, 内吞, TW-37

Abstract: Ｏｂｊｅｃｔｉｖｅ：To investigate effect and mechanism of kidney injury molecule-1 (KIM-1) mediated immunoglobulin free light chains (FLCs) endocytosis on renal tubular injury and fibrosis in renal tubular epithelial cells.
Ｍｅｔｈｏｄｏｌｏｇｙ：(1) urine samples from 4 patients with multiple myeloma were selected and FLCs were purified by ion exchange chromatography;(2) the model of HK-2 cell injury was induced by FLCs extracted by the above method in vitro. FLCs stimulation was continued and KIM-1 inhibitor TW-37 was used to treat it.After continous intraperitoneal injection of FLCs for 14 days into mice in vivo, the animal model of renal tubular injury induced by FLCs was established and interfered with TW-37. The levels of KIM-1, TGF-β etc in HK-2 cells and renal tissue were detected by Western Blot. The Ratio of urinary albumin protein to creatinine and content of KIM-1 in urine were detected by ELISA method, and the degree of renal interstitial fibrosis was detected by Sirius red staining.
Ｒｅｓｕｌｔｓ：(1) in vitro, FLCs stimulated HK-2 cells to increase expression of KIM-1, which was co-localization of KIM-1 and FLCs in HK-2 cells. TW-37 treatment can reduce FLCs endocytosis in HK-2 cells, reduce perinuclear aggregation of lysosomes in renal tubular cells stimulated by FLCs, and reduce expression of oxidative stress and fibrosis indexes. The results of animal model showed that TW-37 can alleviate renal tubular injury induced by FLCs, such as decrease of KIM-1 content in urine and expression of KIM-1 in renal tissue, the decrease of oxidative stress, fibrosis index and collagen deposition in renal tissue.
Ｃｏｎｃｌｕｓｉｏｎ：KIM-1 can mediate endocytosis of FLCs by renal proximal tubular cells, and inhibition of KIM-1 may alleviate renal injury caused by FLCs.

Key words: renal tubular epithelial cell, immunoglobulin free light chain, kidney injury molecule-1, endocytosis, TW-37

董世惠, 范芸, 夏园园, 杨雪, 刘丰, 杨帆, 梁丹丹, 曾彩虹. 肾损伤分子1介导游离轻链内吞致近端肾小管上皮细胞损伤[J]. 肾脏病与透析肾移植杂志, 2023, 32(2): 121-127.

DONG Shihui, FAN Yun, XIA Yuanyuan, YANG Xue, LIU Feng, YANG Fan, LIANG Dandan, ZENG Caihong. Injury of proximal renal tubular epithelial cells induced by kidney injury molecule-1 mediated endocytosis of immunoglobulin free light chain[J]. Chinese Journal of Nephrology, Dialysis & Transplantation, 2023, 32(2): 121-127.

[1]	向近杰, 李颢. 细胞焦亡在草酸钙肾结石形成机制中的研究进展[J]. 肾脏病与透析肾移植杂志, 2023, 32(2): 168-173.
[2]	薛翔, 李世军. 急性肾损伤进展为慢性肾脏病的机制[J]. 肾脏病与透析肾移植杂志, 2023, 32(1): 74-78.
[3]	韦伟, 杨乐天, 赵宇亮. 急性肾损伤中肾小管上皮紧密连接的研究进展[J]. 肾脏病与透析肾移植杂志, 2022, 31(6): 567-572.
[4]	王宇阳，张浩军，路晓光，等. 自噬在糖尿病肾病中的作用[J]. 肾脏病与透析肾移植杂志, 2019, 28(4): 364-368.
[5]	姜雪，李世军. 急性肾损伤肾小管上皮细胞修复的分子机制[J]. 肾脏病与透析肾移植杂志, 2019, 28(1): 83-87.
[6]	张梦希，董伟，梁馨苓. 过氧化物酶体增殖物激活受体γ辅激活物1-α在急性肾损伤中的作用[J]. 肾脏病与透析肾移植杂志, 2018, 27(4): 364-368.
[7]	侯庆，汪玲，张利文，等. 基于硝基还原酶/甲硝唑系统构建斑马鱼急性肾损伤模型[J]. 肾脏病与透析肾移植杂志, 2018, 27(2): 130-134.
[8]	董伟, 张舒, 陈源汉,等. 活性氧自由基在肾小管上皮细胞necroptosis中的作用[J]. 肾脏病与透析肾移植杂志, 2017, 26(3): 246-250.
[9]	于海霞,郭佳,刘东伟,等. 瞬时受体电位离子通道3在糖尿病肾病小鼠的表达及意义[J]. 肾脏病与透析肾移植杂志, 2017, 26(2): 142-147.
[10]	张志诚\|赵文紧\|刘志红\|等. 炎性细胞因子对人肾小管上皮细胞C3a受体表达的调控[J]. 肾脏病与透析肾移植杂志, 2016, 25(2): 134-139.
[11]	陈军童\|苟蓉\|邢玉荣\|等. 肾损伤分子1对高糖诱导人肾小管上皮细胞自噬作用的影响[J]. 肾脏病与透析肾移植杂志, 2015, 24(2): 145-149.
[12]	唐琳，张娜娜，李慧，等. 内皮素-1诱导大鼠肾小管上皮细胞转分化的可能机制[J]. 肾脏病与透析肾移植杂志, 2013, 22(2): 130-133.
[13]	王轩，周益，朱楠，等. 乙型肝炎病毒x基因转染肾小管上皮细胞导致细胞凋亡的机制探讨[J]. 肾脏病与透析肾移植杂志, 2012, 21(6): 507-512.
[14]	凌光辉,唐文彬,孙林,等. Smad锚着蛋白在高糖诱导人肾小管上皮细胞细胞外基质沉积中的作用[J]. 肾脏病与透析肾移植杂志, 2012, 21(4): 346-352.
[15]	孙岩,李瑛,孙林 ,等. 去甲斑蝥素抑制单侧输尿管梗阻大鼠肾小管上皮-间充质转分化的实验研究[J]. 肾脏病与透析肾移植杂志, 2012, 21(1): 46-52.

ISSN 1006-298X CN 32-1425/R

肾损伤分子1介导游离轻链内吞致近端肾小管上皮细胞损伤

Injury of proximal renal tubular epithelial cells induced by kidney injury molecule-1 mediated endocytosis of immunoglobulin free light chain

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