锌指蛋白281抑制高糖诱导的肾小管上皮细胞上皮间质转化和细胞外基质合成

doi:10.11958/20240031

天津医药 ›› 2024, Vol. 52 ›› Issue (7): 720-726.doi: 10.11958/20240031

锌指蛋白281抑制高糖诱导的肾小管上皮细胞上皮间质转化和细胞外基质合成

侯维玲¹(), 乔云阳², 吴小芸², 施会敏², 曲高婷², 张爱青³^,^∆()

1 南京医科大学附属江宁医院儿科（邮编211100）
2 南京医科大学第二附属医院儿科
3 南京医科大学第四附属医院儿科

收稿日期:2024-01-04 修回日期:2024-02-26 出版日期:2024-07-15 发布日期:2024-07-11
通讯作者: ^∆E-mail：njaiqing@njmu.edu.cn
作者简介:侯维玲（1983），女，硕士在读，主要从事儿科学方面研究。E-mail：13770698345@163.com
基金资助:
江苏省医学会儿科医学科研专项基金项目(SYH-32034-0073);南京市卫生科技发展专项资金项目(YKK23209)

Zinc finger protein 281 inhibits high glucose-induced epithelial-mesenchymal transition and extracellular matrix synthesis in renal tubular epithelial cells

HOU Weiling¹(), QIAO Yunyang², WU Xiaoyun², SHI Huimin², QU Gaoting², ZHANG Aiqing³^,^∆()

1 Department of Pediatrics, the Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing 211100, China
2 Department of Pediatrics, the Second Affiliated Hospital of Nanjing Medical University
3 Department of Pediatrics, the Fourth Affiliated Hospital of Nanjing Medical University

Received:2024-01-04 Revised:2024-02-26 Published:2024-07-15 Online:2024-07-11
Contact: ^∆E-mail：njaiqing@njmu.edu.cn

侯维玲, 乔云阳, 吴小芸, 施会敏, 曲高婷, 张爱青. 锌指蛋白281抑制高糖诱导的肾小管上皮细胞上皮间质转化和细胞外基质合成[J]. 天津医药, 2024, 52(7): 720-726.

HOU Weiling, QIAO Yunyang, WU Xiaoyun, SHI Huimin, QU Gaoting, ZHANG Aiqing. Zinc finger protein 281 inhibits high glucose-induced epithelial-mesenchymal transition and extracellular matrix synthesis in renal tubular epithelial cells[J]. Tianjin Medical Journal, 2024, 52(7): 720-726.

摘要/Abstract

摘要：

目的探讨锌指蛋白281（ZNF281）在高糖（HG）诱导的肾小管上皮细胞（RTECs）上皮间质转化（EMT）和细胞外基质（ECM）合成中的作用及机制。方法使用HG诱导RTECs以构建糖尿病肾病模型，分为Control组、HG组和Mannitol组，使用CCK-8检测细胞增殖活力。使用小干扰RNA（siRNA）在HG诱导的RTECs中敲低ZNF281的表达水平，分为Control组、HG组、HG+ZNF281 siRNA组和HG+ZNF281 vector组。使用腺苷单磷酸活化蛋白激酶（AMPK）激动剂阿卡地新（AICAR）活化AMPK，分为Control组、HG组、HG+AICAR组和HG+二甲基亚砜组。实时荧光定量PCR和蛋白免疫印迹法检测ZNF281、EMT和ECM合成相关指标表达水平。结果与Control组相比，HG组ZNF281、波形蛋白（vimentin）、α-平滑肌肌动蛋白（α-SMA）、纤维连接蛋白（FN）和Ⅰ型胶原蛋白（ColⅠ）的蛋白和mRNA表达水平升高，E-钙黏蛋白（E-cadherin）表达水平降低；与HG组相比，HG+ZNF281 siRNA组和HG+AICAR组的EMT和ECM合成相关指标的蛋白和mRNA表达水平发生明显变化，同时HG+AICAR组ZNF281的蛋白和mRNA表达水平较HG组降低；在使用AICAR和转染ZNF281过表达质粒共处理的细胞中，AICAR+ZNF281组vimentin、α-SMA、FN、ColⅠ的表达水平较空载组升高，E-cadherin表达水平降低。结论 AMPK通过负向调控ZNF281的表达水平进而抑制HG诱导的RTECs中EMT和ECM合成。

关键词: 糖尿病肾病, Tristetraprolin蛋白, 上皮-间质转化, 细胞外基质, AMP活化蛋白激酶类, 肾小管间质纤维化, 锌指蛋白281

Abstract:

Objective To investigate the role and mechanism of zinc finger protein 281 (ZNF281) in high glucose (HG)-induced epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) synthesis in renal tubular epithelial cells (RTECs). Methods HG induced RTECs were used to construct a diabetic kidney disease cell model, and cells were divided into the control group, the HG group and the mannitol group. Cell proliferation viability was detected by CCK-8. The expression of ZNF281 was knocked down in HG-treated RTECs using small interfering RNA (siRNA). HG-induced RTECs after knockdown of ZNF281 were divided into the control group, the HG group, the HG+ZNF281 siRNA group and the HG+ZNF281 vector group. Adenosine monophosphate-activated protein kinase (AMPK) was activated using AMPK agonist, acadexin (AICAR), and then cells were divided into the control group, the HG group, the HG+AICAR group and the HG+dimethyl sulfoxide group. The expression levels of ZNF281, EMT and ECM synthesis-related indexes were detected by qPCR and Western blot assay. Results Compared with the control group, the protein and mRNA expression levels of vimentin, α-smooth muscle actin (α-SMA), fibronectin (FN) and collagen Ⅰ (Col Ⅰ) were significantly higher, and the expression of E-cadherin was significantly lower in the HG group. Compared with the HG group, the protein and mRNA expression levels of EMT and ECM synthesis-related indexes were significantly changed in the HG+ZNF281 siRNA group and the HG+AICAR group. The protein and mRNA expression levels of ZNF281 were significantly reduced in the HG+AICAR group compared with the HG group. In cells co-treated with AICAR and transfected with ZNF281 plasmid, the expression levels of vimentin, α-SMA, FN and Col Ⅰ were significantly higher in the AICAR+ZNF281 group, and E-cadherin was significantly lower compared with that of the vector group. Conclusion AMPK inhibits EMT and ECM synthesis in HG-treated RTECs by negatively regulating the expression level of ZNF281.

Key words: diabetic nephropathies, tristetraprolin, epithelial-mesenchymal transition, extracellular matrix, AMP-activated protein kinases, tubulointerstitial fibrosis, zinc finger protein 281

中图分类号:

R587.24，R34

图/表 12

参考文献 24

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基因名称	引物序列（5′→3′）	产物大小/bp
ZNF281	上游：GCCATCCTCTCCCCAAGTC 下游：GAGCTTCGGAAAGCAGCACTA	65
E-cadherin	上游：TCGGAAGACTCCCGATTCAAA 下游：CGGACGAGGAAACTGGTCTC	95
vimentin	上游：CGTCCACACGCACCTACAG 下游：GGGGGATGAGGAATAGAGGCT	74
α-SMA	上游：CAGCAAACAGGAATACGACGAA 下游：AACCACGAGTAACAAATCAAAGC	168
FN	上游：GCAAGAAGGACAACCGAGGAAA 下游：GGACATCAGTGAAGGAGCCAGA	126
ColⅠ	上游：GCTCCTCTTAGGGGCCACT 下游：ATTGGGGACCCTTAGGCCAT	91
β-actin	上游：CATCCGTAAAGACCTCTATGCCAAC 下游：ATGGAGCCACCGATCCACA	171

基因名称	引物序列（5′→3′）	产物大小/bp
ZNF281	上游：GCCATCCTCTCCCCAAGTC 下游：GAGCTTCGGAAAGCAGCACTA	65
E-cadherin	上游：TCGGAAGACTCCCGATTCAAA 下游：CGGACGAGGAAACTGGTCTC	95
vimentin	上游：CGTCCACACGCACCTACAG 下游：GGGGGATGAGGAATAGAGGCT	74
α-SMA	上游：CAGCAAACAGGAATACGACGAA 下游：AACCACGAGTAACAAATCAAAGC	168
FN	上游：GCAAGAAGGACAACCGAGGAAA 下游：GGACATCAGTGAAGGAGCCAGA	126
ColⅠ	上游：GCTCCTCTTAGGGGCCACT 下游：ATTGGGGACCCTTAGGCCAT	91
β-actin	上游：CATCCGTAAAGACCTCTATGCCAAC 下游：ATGGAGCCACCGATCCACA	171

组别	mRNA（n=4）
组别	ZNF281	E-cadherin	vimentin	α-SMA	FN	ColⅠ
Control组	1.04±0.32	1.02±0.21	1.07±0.45	1.02±0.22	1.01±0.13	1.03±0.30
HG组	2.37±0.52^a	0.49±0.08^a	2.39±0.58^a	1.97±0.29^a	2.18±0.45^a	1.75±0.08^a
Mannitol组	1.02±0.30	0.86±0.05	0.96±0.26	1.18±0.22	0.96±0.30	0.94±0.35
F	15.580^＊＊	17.020^＊＊	12.560^＊＊	17.180^＊＊	18.780^＊＊	10.890^＊＊
组别	蛋白（n=3）
组别	ZNF281	E-cadherin	vimentin	α-SMA	FN	Col Ⅰ
Control组	1.00±0.18	1.00±0.21	1.00±0.18	1.00±0.13	1.00±0.09	1.00±0.13
HG组	2.11±0.15^a	0.33±0.11^a	1.71±0.06^a	1.60±0.10^a	1.38±0.07^a	1.33±0.10^a
Mannitol组	0.92±0.33	0.98±0.13	1.01±0.39	0.92±0.18	0.97±0.08	0.78±0.17
F	23.900^＊＊	17.420^＊＊	8.034^＊	21.650^＊＊	22.990^＊＊	12.290^＊＊

组别	mRNA（n=4）
组别	ZNF281	E-cadherin	vimentin	α-SMA	FN	ColⅠ
Control组	1.04±0.32	1.02±0.21	1.07±0.45	1.02±0.22	1.01±0.13	1.03±0.30
HG组	2.37±0.52^a	0.49±0.08^a	2.39±0.58^a	1.97±0.29^a	2.18±0.45^a	1.75±0.08^a
Mannitol组	1.02±0.30	0.86±0.05	0.96±0.26	1.18±0.22	0.96±0.30	0.94±0.35
F	15.580^＊＊	17.020^＊＊	12.560^＊＊	17.180^＊＊	18.780^＊＊	10.890^＊＊
组别	蛋白（n=3）
组别	ZNF281	E-cadherin	vimentin	α-SMA	FN	Col Ⅰ
Control组	1.00±0.18	1.00±0.21	1.00±0.18	1.00±0.13	1.00±0.09	1.00±0.13
HG组	2.11±0.15^a	0.33±0.11^a	1.71±0.06^a	1.60±0.10^a	1.38±0.07^a	1.33±0.10^a
Mannitol组	0.92±0.33	0.98±0.13	1.01±0.39	0.92±0.18	0.97±0.08	0.78±0.17
F	23.900^＊＊	17.420^＊＊	8.034^＊	21.650^＊＊	22.990^＊＊	12.290^＊＊

组别	mRNA（n=4）
组别	ZNF281	E-cadherin	vimentin	α-SMA	FN	Col Ⅰ
Control组	1.02±0.25	1.04±0.31	1.03±0.27	1.02±0.21	1.01±0.15	1.01±0.19
HG组	2.17±0.63^a	0.43±0.07^a	2.08±0.21^a	2.09±0.19^a	2.18±0.15^a	2.06±0.18^a
HG+ZNF281 siRNA组	0.42±0.10^b	0.85±0.08^b	1.55±0.32^b	1.39±0.37^b	1.45±0.22^b	1.60±0.21^b
HG+ZNF281 vector组	2.06±0.50	0.51±0.07	2.29±0.24	2.29±0.46	2.26±0.32	2.07±0.14
F	15.830^＊＊	11.750^＊＊	18.320^＊＊	13.230^＊＊	29.910^＊＊	30.500^＊＊
组别	蛋白（n=3）
组别	ZNF281	E-cadherin	vimentin	α-SMA	FN	Col Ⅰ
Control组	1.00±0.27	1.00±0.09	1.00±0.17	1.00±0.11	1.00±0.08	1.00±0.10
HG组	2.39±0.33^a	0.58±0.03^a	1.74±0.15^a	1.62±0.13^a	1.44±0.13^a	1.32±0.03^a
HG+ZNF281 siRNA组	1.24±0.57^b	0.76±0.08^b	1.17±0.25^b	1.09±0.24^b	1.10±0.14^b	0.97±0.10^b
HG+ZNF281 vector组	2.71±0.43	0.43±0.07	1.57±0.20	1.46±0.37	1.35±0.07	1.20±0.06
F	12.220^＊＊	36.510^＊＊	9.089^＊＊	4.662^＊	10.870^＊＊	13.220^＊＊

锌指蛋白281抑制高糖诱导的肾小管上皮细胞上皮间质转化和细胞外基质合成

Zinc finger protein 281 inhibits high glucose-induced epithelial-mesenchymal transition and extracellular matrix synthesis in renal tubular epithelial cells

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组别		mRNA（n=4）
组别		ZNF281		E-cadherin		vimentin		α-SMA		FN		Col Ⅰ
Control组		1.02±0.26		1.04±0.32		1.01±0.14		1.02±0.23		1.04±0.30		1.06±0.38
HG组		2.45±0.47^a		0.49±0.10^a		2.42±0.26^a		2.19±0.34^a		2.28±0.26^a		2.21±0.42^a
HG+AICAR组		1.42±0.25^b		0.96±0.18^b		1.15±0.28^b		1.26±0.27^b		1.54±0.09^b		1.34±0.23^b
HG+DMSO组		2.47±0.33		0.52±0.09		2.55±0.22		2.08±0.37		2.31±0.24		2.09±0.49
F		18.670^＊＊		8.867^＊＊		50.250^＊＊		14.270^＊＊		27.380^＊＊		8.217^＊＊
组别	蛋白（n=3）
组别	ZNF281		p-AMPK/AMPK		E-cadherin		vimentin		α-SMA		FN		Col Ⅰ
Control组	1.00±0.12		1.00±0.22		1.00±0.06		1.00±0.16		1.00±0.19		1.00±0.17		1.00±0.15
HG组	1.60±0.14^a		0.62±0.10^a		0.47±0.10^a		1.62±0.16^a		1.94±0.34^a		1.71±0.24^a		1.66±0.14^a
HG+AICAR组	1.29±0.09^b		0.96±0.05^b		0.92±0.27^b		0.81±0.20^b		1.25±0.27^b		1.17±0.16^b		1.09±0.14^b
HG+DMSO组	1.78±0.15		0.68±0.11		0.43±0.20		1.52±0.25		1.74±0.34		1.68±0.28		1.79±0.17
F	21.810^＊＊		6.068^＊		8.393^＊＊		12.340^＊＊		6.541^＊		8.159^＊＊		20.960^＊＊

组别		mRNA（n=4）
组别		ZNF281		E-cadherin		vimentin		α-SMA		FN		Col Ⅰ
Control组		1.02±0.26		1.04±0.32		1.01±0.14		1.02±0.23		1.04±0.30		1.06±0.38
HG组		2.45±0.47^a		0.49±0.10^a		2.42±0.26^a		2.19±0.34^a		2.28±0.26^a		2.21±0.42^a
HG+AICAR组		1.42±0.25^b		0.96±0.18^b		1.15±0.28^b		1.26±0.27^b		1.54±0.09^b		1.34±0.23^b
HG+DMSO组		2.47±0.33		0.52±0.09		2.55±0.22		2.08±0.37		2.31±0.24		2.09±0.49
F		18.670^＊＊		8.867^＊＊		50.250^＊＊		14.270^＊＊		27.380^＊＊		8.217^＊＊
组别	蛋白（n=3）
组别	ZNF281		p-AMPK/AMPK		E-cadherin		vimentin		α-SMA		FN		Col Ⅰ
Control组	1.00±0.12		1.00±0.22		1.00±0.06		1.00±0.16		1.00±0.19		1.00±0.17		1.00±0.15
HG组	1.60±0.14^a		0.62±0.10^a		0.47±0.10^a		1.62±0.16^a		1.94±0.34^a		1.71±0.24^a		1.66±0.14^a
HG+AICAR组	1.29±0.09^b		0.96±0.05^b		0.92±0.27^b		0.81±0.20^b		1.25±0.27^b		1.17±0.16^b		1.09±0.14^b
HG+DMSO组	1.78±0.15		0.68±0.11		0.43±0.20		1.52±0.25		1.74±0.34		1.68±0.28		1.79±0.17
F	21.810^＊＊		6.068^＊		8.393^＊＊		12.340^＊＊		6.541^＊		8.159^＊＊		20.960^＊＊

组别	mRNA（n=4）
组别	ZNF281			E-cadherin		vimentin		α-SMA		FN		ColⅠ
AICAR+ZNF281 vector组	1.05±0.39			1.03±0.24		1.03±0.26		1.01±0.17		1.01±0.19		1.03±0.25
AICAR+ZNF281组	49.05±9.96			0.60±0.20		1.77±0.24		1.46±0.18		1.98±0.38		1.95±0.33
t	9.628^＊＊			2.763^＊		4.170^＊＊		3.673^＊		4.523^＊＊		4.435^＊＊
组别		蛋白（n=3）
组别		ZNF281	E-cadherin		vimentin		α-SMA		FN		ColⅠ
AICAR+ZNF281 vector组		1.00±0.11	1.00±0.10		1.00±0.22		1.00±0.15		1.00±0.05		1.00±0.13
AICAR+ZNF281组		1.40±0.21	0.38±0.16		1.67±0.27		1.89±0.49		1.81±0.36		2.12±0.48
t		2.964^＊	5.674^＊＊		3.290^＊		3.022^＊		3.895^＊		3.909^＊

组别	mRNA（n=4）
组别	ZNF281			E-cadherin		vimentin		α-SMA		FN		ColⅠ
AICAR+ZNF281 vector组	1.05±0.39			1.03±0.24		1.03±0.26		1.01±0.17		1.01±0.19		1.03±0.25
AICAR+ZNF281组	49.05±9.96			0.60±0.20		1.77±0.24		1.46±0.18		1.98±0.38		1.95±0.33
t	9.628^＊＊			2.763^＊		4.170^＊＊		3.673^＊		4.523^＊＊		4.435^＊＊
组别		蛋白（n=3）
组别		ZNF281	E-cadherin		vimentin		α-SMA		FN		ColⅠ
AICAR+ZNF281 vector组		1.00±0.11	1.00±0.10		1.00±0.22		1.00±0.15		1.00±0.05		1.00±0.13
AICAR+ZNF281组		1.40±0.21	0.38±0.16		1.67±0.27		1.89±0.49		1.81±0.36		2.12±0.48
t		2.964^＊	5.674^＊＊		3.290^＊		3.022^＊		3.895^＊		3.909^＊