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Journal of Central South University Medical Sciences logoLink to Journal of Central South University Medical Sciences
. 2021 Jun 28;46(6):601–608. [Article in Chinese] doi: 10.11817/j.issn.1672-7347.2021.201008

自噬通过抑制上皮间质转化减轻梗阻性肾病肾纤维化

Autophagy attenuates renal fibrosis in obstructive nephropathy through inhibiting epithelial-to-mesenchymal transition

ZHANG Bo 1,2, RU Feng 1, CHEN Xiang 1, CHEN Zhi 1,✉
Editor: 傅 希文
PMCID: PMC10930200  PMID: 34275928

Abstract

Objective

To explore the relationship between autophagy and epithelial-to-mesenchymal transition (EMT), and to evaluate whether autophagy can affect the progression of renal fibrosis in obstructive nephropathy by regulating the EMT process.

Methods

Unilateral ureteral obstruction (UUO) renal fibrosis model of rat was constructed, and the animals were divided into a sham group, an UUO group, an UUO+low-dose rapamycin group, and an UUO+high-dose rapamycin group. HE staining was used to observe the structure of the kidney, and Masson staining was used to observe renal interstitial collagen deposition. The expressions of E-cadherin, alpha-smooth muscle actin (α-SMA), Snail 1, and microtubule-associated protein-1 light chain 3II (LC3II) were detected by Western blotting, reflecting cellular EMT and autophagy. Transforming growth factor β1 (TGF-β1) induced-NRK52E cells model was constructed, and the cells were divided into a control group, a TGF-β1 group, and a TGF-β1+ Snail 1 siRNA group. To explore the effect of autophagy on EMT, the cells were also divided into a control group, a rapamycin group, and a Beclin 1 siRNA group. Western blotting was used to detect the expressions of E-cadherin, α-SMA, Snail 1, LC3II, collagen I, and fibronectin.

Results

Compared with the sham group, the kidney damage in the UUO group was significantly worse; compared with the sham group, the collagen deposition in the kidney tissues in the UUO group was significantly increased, which were significantly reduced in the UUO+high-dose rapamycin group and the UUO+low-dose rapamycin group compared with the UUO group; compared with the sham group, the E-cadherin level in the kidney of the UUO group was significantly reduced, and the expression levels of α-SMA and LC3II were significantly increased (all P<0.05). Compared with the UUO group, the expression levels of E-cadherin and LC3II in the UUO+high-dose rapamycin group and the UUO+low-dose rapamycin group were significantly increased (P<0.01 and P<0.05, respectively), and the expression level of α-SMA was significantly decreased (P<0.01 and P<0.05, respectively). The expression levels of Snail 1, α-SMA, collagen I and fibronectin were significantly higher, and the E-cadherin level was significantly lower in the TGF-β1 group than those in the control group (all P<0.05). Compared with the TGF-β1 group, the expression of E-cadherin was increased significantly, and the expressions of α-SMA, collagen I and fibronectin were decreased significantly in the TGF-β1+Snail 1 siRNA group (all P<0.05). Compared with the control group, the expression levels of LC3II and E-cadherin were significantly elevated, and the expression levels of α-SMA and Snail 1 in the rapamycin group were significantly reduced (all P<0.05); the expression levels of LC3II and E-cadherin were significantly reduced, and the expression levels of α-SMA and Snail 1 were significantly increased in the Beclin 1 siRNA group (all P<0.05).

Conclusion

Autophagy plays an essential role in the regulation of EMT in obstructive nephropathy fibrosis. Autophagy can alleviate renal fibrosis by inhibiting EMT.

Keywords: autophagy, epithelial-to-mesenchymal transition, renal fibrosis

梗阻性肾病是由于泌尿道结构功能异常、尿液排出受阻、肾结构功能破坏，最终导致肾功能衰竭的一类疾病，肾小管间质纤维化是梗阻性肾病最显著的病理学表现[1-2]。上皮间质转化(epithelial-mesen-chymal transition，EMT)是指在某些病理情况下，上皮细胞特异性分子表达减少，细胞骨架改变，细胞失去其原有上皮特征转变为间质的表型，同时发生细胞极性改变，失去与基底膜的连接，从而使形态、功能及分子表达向间质细胞转变的过程[3]。研究[4-5]发现EMT在纤维化疾病中发挥重要的促进作用。自噬是细胞重要的自我净化过程，用于修复细胞损伤和维持代谢平衡，自噬具有促进细胞生长和凋亡的双重作用，其效应取决于细胞的类型和刺激强度[6]。然而EMT与自噬的关系鲜有报道。本研究旨在探讨细胞自噬与EMT之间的关系，以及自噬是否可以通过调节EMT进程影响梗阻性肾病肾纤维化进展。

1. 材料与方法

1.1. 材料

1.1.1. 细胞及主要试剂

大鼠肾小管上皮细胞NRK-52E购自美国模式菌种收集中心细胞库；雷帕霉素、转化生长因子-β1(transforming growth factor-β1，TGF-β1)购自中国上海MCE公司；钙黏附蛋白E(E-cadherin)、α平滑肌肌动蛋白(alpha-smooth muscle actin，α-SMA)、锌指转录因子(Snail 1)、I型胶原(collagen I)、纤维黏连蛋白(fibronectin)、微管相关蛋白1轻链3II(microtubule-associated protein-1 light chain 3II，LC3II)、内参actin抗体和羊抗兔或羊抗鼠IgG二抗购自武汉谷歌生物科技有限公司；胎牛血清购自澳大利亚CellMax公司；DME-F/12培养基购自美国Hyclone公司；Snaill siRNA及自噬效应蛋白Beclin 1 siRNA 购自美国Thermo Scientific公司。

1.1.2. 实验动物

雄性Sprague-Dawley(SD)大鼠，8周龄，体重200~220 g，从湖南省斯莱克景达实验动物有限公司订购，动物饲养在12 h/12 h的光/暗循环和温度控制在(23±1) ℃的清洁动物房。实验方案及操作过程经中南大学动物实验伦理委员会批准。

1.2. 方法

1.2.1. 动物分组及模型制备

实验大鼠适应性喂养1周后，随机分为假手术组、单侧输尿管梗阻(unilateral urethralobstruction，UUO)组、UUO+低剂量雷帕霉素组、UUO+高剂量雷帕霉素组，每组大鼠均为10只。UUO模型造模过程如下：用3%戊巴比妥钠溶液(0.5 mL/100 g)腹腔注射麻醉大鼠，剪开大鼠背部中下部皮肤、筋膜及肌肉，显露出左侧肾，用玻璃分针沿肾下级分离暴露左侧输尿管，用2根4-0丝线进行结扎，在2根结扎线之间离断输尿管以防止逆行性尿路感染。用庆大霉素充分冲洗伤口后吸净，逐层缝合伤口。假手术组仅分离出左侧输尿管但不结扎，其余操作与造模组完全相同；UUO组每天腹腔注射等量生理盐水；UUO+低剂量雷帕霉素组大鼠手术后连续14 d腹腔注射雷帕霉素[1 mg/(kg·d)]；UUO+高剂量雷帕霉素组大鼠手术后连续14 d腹腔注射雷帕霉素[2 mg/(kg·d)]。术后14 d处死所有大鼠。

1.2.2. 细胞培养及处理

正常大鼠肾上皮细胞系NRK-52E用含10%胎牛血清的DME-F/12培养基培养在37 ℃、5% CO2的培养箱中。用1%胎牛血清制备的2 ng/mL的TGF-β1处理细胞24 h以诱导EMT。Snail 1是EMT进程中的关键调节因子，将Snail 1 siRNA与转染试剂混合于100 μL无血清培养基中，滴加于NRK52E细胞上转染Snail 1 siRNA以沉默EMT进程；转染后，细胞在含血清的培养基中处理1 h，48 h后收集细胞，蛋白质印迹法证实基因被敲除。将细胞再分为对照组、TGF-β1组、TGF-β1+Snail 1 siRNA组。雷帕霉素是一种常用的自噬激活剂[7]；Beclin 1是自噬关键调控蛋白, 沉默Beclin 1可以有效抑制细胞自噬[8]。细胞培养液中加入浓度为20 nmol/L的雷帕霉素以促进细胞自噬；按照生产厂家的说明书，用Beclin 1 siRNA转染细胞抑制细胞自噬。将细胞再分为对照组、雷帕霉素组、Beclin 1 siRNA组。LC3II是细胞自噬标志物，通过检测LC3II的表达水平可以反映细胞自噬的上调和下调[9]。

1.2.3. HE染色和Masson染色

将肾组织固定在4%多聚甲醛溶液并包埋在石蜡中，依次烤片、脱蜡及水化。HE染色：将已经水化的切片放入苏木精溶液中染色数分钟，冲洗后将切片置于酒精中分色，先将切片放入70%和90%酒精中脱水数分钟，然后将切片置于伊红中染色；Masson染色：用苏木精和伊红混合溶液染色3 min，丽春红溶液清洗5 min，磷钼酸溶液染色2 min和胺蓝液复染5 min。然后再脱水、透明、封片，并在显微镜下观察拍照。

1.2.4. 蛋白质印迹法检测蛋白质表达

弃细胞上清液，用预冷的PBS洗涤2~3次，加入适量RIPA细胞裂解液，混匀，冰上裂解30 min，于4 ℃以12 000 g离心20 min；将上清转移至新的EP管，并测定蛋白质浓度，加入5×蛋白上样缓冲液 25 μL，混匀后100 ℃金属浴10 min，使蛋白质变性。制备的蛋白质样本先经10% 十二烷基硫酸钠聚丙烯酰胺凝胶电泳(sodium dodecyl sulfate salt-polyacrylamide gel elec-trophoresis，SDS-PAGE)分离，然后以200 mA电流转膜45 min，将蛋白质转移至聚偏二氟乙烯膜上；在5%脱脂奶粉的封闭液中室温封闭1 h；加入1꞉500稀释的一抗(E-cadherin、α-SMA、Snail 1、collagen I、fibronectin、LC3II和actin)，在4 ℃条件下反应过夜；加入辣根过氧化物酶标记的羊抗兔或羊抗鼠IgG二抗(1꞉10 000)，在室温下反应l h(每次操作后用TBST洗涤缓冲液漂洗3次，每次10 min)，加入化学发光试剂进行显影成像，采用Image J软件分析所获得的图像，各目的基因与tubulin 灰度比值为蛋白质的相对表达水平。

1.3. 统计学处理

使用GraphPad Prism统计学软件进行数据分析，所有实验数据以均数±标准差( x¯ ±s)表示，采用t检验比较两组的差异，采用单因素方差分析比较多组的差异，P<0.05为差异有统计学意义。

2. 结 果

2.1. UUO模型中EMT被显著激活

HE染色显示：假手术组肾小球和肾小管结构正常，但呈紧密堆积，UUO组肾间质空间明显变宽，炎性细胞和血管周围渗出物浸润增加，肾小管细胞发生坏死和萎缩；Masson染色显示：假手术组胶原沉积非常少，UUO组的肾组织中胶原沉积明显增加(图1A)，显示造模成功。蛋白质印迹法结果显示：与假手术组相比，UUO组肾中上皮细胞标志物 E-cadherin水平明显降低，间质细胞标志物α-SMA水平明显升高(均P<0.05，图1B)。

图1.

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UUO模型中EMT被显著激活

Figure 1 EMT was significantly activated in the UUO model

A: Representative histological images of kidney sections in the sham group and the UUO group (HE staining and Masson staining, ×400); B: Protein expression levels of α-SMA and E-cadherin in the sham group and the UUO group by Western blotting and densitometric analysis. *P<0.05 vs the sham group.

2.2. 抑制EMT可以减轻TGF-β1诱导的NRK52E细胞的纤维化

蛋白质印迹法显示：TGF-β1组中Snail 1、α-SMA、collagen I和fibronectin表达水平显著高于对照组，E-cadherin水平明显低于对照组(均P<0.05)。与TGF-β1组相比，TGF-β1+Snail 1 siRNA组E-cadherin的表达显著增加，Snail 1、α-SMA、collagen I和fibronectin表达显著减少(均P<0.05，图2)。

图2.

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NRK52E细胞中EMT及反映纤维化的蛋白质表达水平

Figure 2 EMT and protein level of fibrosis markers in NRK52E cells

A: Expression of Snail 1, α-SMA, E-cadherin, collagen I, and fibronectin in the control group, the TGF-β1 group and the TGF-β1+Snail 1 siRNA group by Western blotting; B: Densitometric analysis of Snail 1; C: Densitometric analysis of α-SMA; D: Densitometric analysis of E-cadherin; E: Densitometric analysis of collagen I; F: Densitometric analysis of fibronectin. *P<0.05 vs the control group; †P<0.05 vs the TGF-β1 group.

2.3. 改变自噬活性可以影响NRK52E细胞的EMT进程

蛋白质印迹法显示：雷帕霉素组LC3II的表达显著高于对照组，Beclin 1 siRNA组LC3II的表达水平低于对照组(均P<0.05；图3A，3B)。E-cadherin在雷帕霉素组的表达最高，其次是对照组和Beclin 1 siRNA组(均P<0.05；图3A，3C)。α-SMA在Beclin 1 siRNA组中呈高表达，在雷帕霉素组和对照组中表达明显降低(均P<0.05；图3A，3D)。与对照组相比，Beclin 1 siRNA组Snail 1的表达显著增加，雷帕霉素组Snail 1的表达显著降低(均P<0.05；图3A，3E)。

图3.

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改变自噬活性后EMT及反映自噬的蛋白质水平的表达

Figure 3 Expression of protein levels of autophagy and EMT markers after altering autophagy activity in NRK52E cells

A: Expression of LC3II, E-cadherin, α-SMA, and Snail 1 in the rapamycin group, the control group, and the Beclin 1 siRNA group by Western blotting; B: Densitometric analysis of LC3II; C: Densitometric analysis of E-cadherin; D: Densitometric analysis of α-SMA; E: Densitometric analysis of Snail 1. *P<0.05 vs the control group.

2.4. 雷帕霉素可以抑制UUO大鼠EMT从而减轻肾纤维化

蛋白质印迹法显示：LC3II水平在UUO+高剂量雷帕霉素组最高，其次是UUO+低剂量雷帕霉素组、UUO组和假手术组，差异均有统计学意义(均P<0.05；图4A，4B)，显示雷帕霉素呈剂量依赖性促进自噬。E-cadherin水平在假手术组最高，UUO+高剂量雷帕霉素组略有下降，UUO+低剂量雷帕霉素组和UUO组表达明显降低，而α-SMA的表达刚好相反(图5)。Masson染色显示：假手术组几乎没有间质胶原沉积，UUO组胶原沉积最明显，UUO+高剂量雷帕霉素组和UUO+低剂量雷帕霉素组胶原沉积较UUO组明显减轻，差异均有统计学意义(均P<0.05，图5)。

图4.

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雷帕霉素以剂量依赖性方式促进大鼠自噬

Figure 4 Autophagy is promoted by rapamycin in a dose-dependent manner in rats

A: Protein level alteration of LC3II in response to different concentration of rapamycin; B: Densitometric analysis of LC3II. *P<0.05 vs the sham group; †P<0.05 vs the UUO group; ‡P<0.05 vs the low-dose rapamycin group.

图5.

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注射雷帕霉素可以抑制UUO大鼠EMT并减轻体内肾纤维化

Figure 5 Injecting rapamycin can attenuate EMT transition in UUO rats and alleviate renal fibrosis in vivo

A: Representative histological images of kidney sections in the sham group, the UUO group, the UUO+low-dose rapamycin group, and the UUO+high-dose rapamycin group (Masson staining, ×200); B: Protein expression of E-cadherin and α-SMA in the sham group, the UUO group, the UUO+low-dose rapamycin group, and the UUO+high-dose rapamycin group by Western blotting; C: Densitometric analysis of E-cadherin; D: Densitometric analysis of α-SMA. *P<0.05 vs the sham group; †P<0.05 vs the UUO+high-dose rapamycin group; ‡P<0.05 vs the UUO+low-dose rapamycin group.

3. 讨 论

肾纤维化是梗阻性肾病发展过程中的主要病理过程，其特征是正常肾结构破坏，成纤维细胞增生，细胞外基质的过度沉积[10]。肾纤维化的发生机制尚未完全阐明。肾小管和肾小管间质占肾组织的很大一部分，是对缺氧、缺血、蛋白尿、毒素和代谢异常等的主要反应部位。越来越多的证据[11-12]表明：肾小管上皮细胞在肾损伤后修复及进展为慢性肾病的过程中起着重要作用，目前认为肾小管上皮细胞受损是肾纤维化的始动因素。当肾小管上皮细胞受损时，肾小管上皮细胞可以发生EMT，转分化为间充质细胞，成为肾组织中成纤维细胞的来源之一[13]。TGF-β1是促进肾纤维化的关键因子，TGF-β1能够激发与细胞外基质沉积有关的多条通路[14]。TGF-β1在EMT发生中的作用已非常明确，研究[15]发现90%以上的EMT的发生都受到TGF-β的直接或间接诱导，TGF-β1高表达可能对EMT具有抑制作用。转录因子Snail 1是一种含有锌指结构的DNA结合蛋白，是诱导EMT的关键促进调节因子，TGF-β1可以通过诱导Snail 1的表达来促进EMT的进程，从而促进肾纤维化[16]。自噬是细胞对有害物质的一种分解代谢过程，通过调节细胞的存活与死亡在维持细胞稳态中发挥重要作用。近年来，有研究[17]发现通过诱导上皮细胞自噬可以减轻肾间质纤维化。然而，其详细机制尤其是肾纤维化发展过程中自噬和EMT的关系尚不清楚。本研究通过体内和体外实验，探讨EMT在肾纤维化中的作用，以及EMT是否在肾小管间质纤维化发展过程中受到自噬的调节。

本研究首先证实了梗阻引起的肾纤维化过程中EMT的存在及其在肾纤维化中的作用，发现在纤维化的肾组织中EMT的特异性标志物显著激活，在此基础上，通过细胞实验敲减Snail 1基因，发现与对照组相比，纤维化标志物明显减少，提示EMT是肾纤维化进展中不可或缺的环节。接下来探讨了自噬与EMT的关系，通过使用雷帕霉素与敲除Beclin 1基因来作为上调或下调自噬水平的方法，发现EMT过程受到自噬的负调控，雷帕霉素可以通过增强自噬和抑制EMT而减轻梗阻性肾病肾纤维化。

众所周知，自噬对于维持细胞代谢至关重要。抑制自噬会使细胞易受应激刺激而无法提供恢复细胞平衡和正常功能所必需的高能量需求，但增强细胞自噬水平也许会给细胞修复和恢复上皮特性带来合适的环境。尽管EMT和自噬在肾疾病中的关系尚不明确，但已有研究关注它们在其他纤维化疾病中的关系，如Grassi等[18]在体内探索了肝细胞的自噬功能，发现抑制自噬可以降低上皮标志物的表达，并增加间充质标志物的水平，故认为自噬通过抑制间充质编程来促进肝细胞的上皮特性。Zou等[19]揭示自噬是抗EMT的细胞保护机制，其通过降解Snail 1蛋白来促进血管生成。在疾病的机制方面这些研究存在差异，但关于自噬对EMT影响的结论几乎相同。本研究证实了自噬可能在肾纤维化中对EMT的抑制作用，为解决肾疾病的纤维化提供了一种可能的新思路。

综上所述，本研究表明自噬在梗阻性肾病纤维化的EMT调控中发挥了重要作用。上调自噬可以抑制EMT，从而减轻肾纤维化的进程。

基金资助

湖南省自然科学基金(2020JJ4870)。

This work was supported by the Natural Science Foundation of Hunan Province, China (2020JJ4870).

利益冲突声明

作者声称无任何利益冲突。

原文网址

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/202106601.pdf

参考文献

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