外周血单核细胞DNMT1及血清IL-6在糖尿病肾脏病中的表达及意义

doi:10.11958/20220812

摘要/Abstract

摘要：

目的探讨外周血单核细胞DNA甲基化转移酶1（DNMT1）及血清白介素-6（IL-6）在糖尿病肾脏病（DKD）中的表达及临床意义。方法选取150例DKD患者（DKD组）及50例同期健康体检者（对照组）。比较2组IL-6、DNMT1、总胆固醇、三酰甘油、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、血肌酐、空腹血糖、肾小球滤过率估计值（eGFR）、24 h尿白蛋白排泄率（24 h UAER）的差异。Pearson相关分析IL-6、DNMT1与其他临床指标的相关性。多因素Logistic回归分析DKD发生的影响因素。受试者工作特征（ROC）曲线分析24 h UAER、IL-6、DNMT1及联合检测对DKD的诊断价值。结果与对照组比较，DKD组的空腹血糖、IL-6、DNMT1、血肌酐、24 h UAER、LDL-C、糖化血红蛋白水平升高，而eGFR、HDL-C水平降低（均P<0.05）。DKD组的IL-6与DNMT1呈正相关（r=0.560，P<0.05）；且IL-6、DNMT1与24 h UAER呈正相关（r分别为0.551和0.570，P<0.05）。24 h UAER、IL-6及DNMT1升高是影响DKD发生的独立危险因素（P<0.05）。24 h UAER、IL-6、DNMT1联合检测诊断DKD的曲线下面积优于单一指标检测。结论 DKD患者DNMT1、IL-6水平升高，24 h UAER、DNMT1、IL-6联合检测可作为临床诊断DKD的良好指标。

关键词: 糖尿病肾病, 早期诊断, 单核细胞, 白细胞介素6, 敏感性与特异性, DNA甲基化转移酶1

Abstract:

Objective To investigate the expression and clinical significance of peripheral blood mononuclear cell DNA methyltransferase 1 (DNMT1) and serum interleukin-6 (IL-6) in diabetic nephropathy (DKD). Methods A total of 150 DKD patients (the DKD group) and 50 healthy subjects (the control group) were selected. Data of IL-6, DNMT1, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), serum creatinine, fasting blood glucose, estimated glomerular filtration rate (eGFR), 24-hour urinary albumin excretion rate (24 h UAER) and other clinical indicators were compared between the two groups. Pearson correlation was used to analyze the correlation between IL-6, DNMT1 and other clinical indicators. Multivariate Logistic regression was used to analyze the influencing factors of DKD. Receiver operating curve (ROC) was used to analyze the diagnostic value of IL-6, DNMT1 and combined detection in DKD. Results Compared with the control group, levels of fasting blood glucose, IL-6, DNMT1, serum creatinine, 24 h UAER, LDL-C and glycosylated hemoglobin were higher in the DKD group, but levels of eGFR and HDL-C were lower (P<0.05). IL-6 was positively correlated with DNMT1 in the DKD group (r=0.560, P<0.05), and IL-6, DNMT1 and 24 h UAER were positively correlated (r=0.551, 0.570, P<0.05). Elevated 24 h UAER, elevated IL-6 and elevated DNMT1 were independent risk factors for DKD (P<0.05). The combined detection of 24 h UAER, IL-6 and DNMT1 in the area under the surface of DKD was significantly higher than that of single index detection. Conclusion DNMT1 and IL-6 are highly expressed in DKD patients, and the combined detection of 24 h UAER, DNMT1 and IL-6 can be used as a good indicator for clinical diagnosis of DKD.

Key words: diabetic nephropathies, early diagnosis, monocytes, interleukin-6, sensitivity and specificity, DNA methyltransferase 1

中图分类号:

R587.2，R692.9

图/表 6

参考文献 18

[1]	傅忱, 胡晓波. 2型糖尿病肾病的临床生化指标变化特征和危险因素探讨[J]. 山西医药杂志, 2021, 50(23):3310-3313.
	FU C, HU X B. Clinical biochemical changes and risk factors of type 2 diabetic nephropathy[J]. Shanxi Medical Journal, 2021, 50(23):3310-3313. doi:10.3969/j.issn.0253-9926.2021.23.029.
[2]	BONNER R, ALBAJRAMI O, HUDSPETH J, et al. Diabetic kidney disease[J]. Prim Care, 2020, 47(4):645-659. doi:10.1016/j.pop.2020.08.004.
[3]	FLISER D, WANNER C. Precision medicine in diabetic nephropathy and chronic kidney disease[J]. Nephrol Dial Transplant, 2021, 36(Suppl 2):10-13. doi:10.1093/ndt/gfaa380.
[4]	MOHAN K N. DNMT1:catalytic and non-catalytic roles in different biological processes[J]. Epigenomics, 2022, 14(10):629-643. doi:10.2217/epi-2022-0035.
[5]	CAI L, ZHAN M, LI Q, et al. DNA methyltransferase DNMT1 inhibits lipopolysaccharide-induced inflammatory response in human dental pulp cells involving the methylation changes of IL-6 and TRAF6[J]. Mol Med Rep, 2020, 21(2):959-968. doi:10.3892/mmr.2019.10860.
[6]	中华医学会糖尿病学分会微血管并发症学组. 中国糖尿病肾脏疾病防治临床指南[J]. 中华糖尿病杂志, 2019, 11(1):15-28.
	Microvascular Complications Group of Diabetes Branch of Chinese Medical Association. Clinical guidelines for prevention and treatment of diabetic kidney disease in China[J]. Chinese Journal of Diabetes, 2019, 11(1):15-28. doi:10.3760/cma.j.issn.1674-5809.2019.01.004.
[7]	薛耀明. 重视糖尿病肾脏病患者的心血管风险评估与管理[J]. 中华糖尿病杂志, 2020, 12(10):761-764.
	XUE Y M. Emphasis on cardiovascular risk assessment and management of patients with diabetic nephropathy[J]. Chinese Journal of Diabetes, 2020, 12(10):761-764. doi:10.3760/cma.j.cn115791-20200831-00543.
[8]	AKHTAR M, TAHA N M, NAUMAN A, et al. Diabetic kidney disease:past and present[J]. Adv Anat Pathol, 2020, 27(2):87-97. doi:10.1097/PAP.0000000000000257.
[9]	LASSEN E, DAEHN I S. Molecular mechanisms in early diabetic kidney disease:glomerular endothelial cell dysfunction[J]. Int J Mol Sci, 2020, 21(24):9456-9462. doi:10.3390/ijms21249456.
[10]	郑芳芳, 周新新, 李晨. 糖尿病肾病患者尿液VCAM-1、IL-6水平变化及与足细胞损伤的相关性研究[J]. 全科医学临床与教育, 2020, 18(12):1076-1079,1083.
	ZHENG F F, ZHOU X X, LI C. Changes of urine VCAM-1 and IL-6 levels and their correlation with podocyte injury in patients with diabetic nephropathy[J]. Clinical Education of General Practice, 2020, 18(12):1076-1079,1083. doi:10.13558/j.cnki.issn1672-3686.2020.012.006.
[11]	FEIGERLOVA E, BATTAGLIA-HSU S F. IL-6 signaling in diabetic nephropathy:From pathophysiology to therapeutic perspectives[J]. Cytokine Growth Factor Rev, 2017, 37(6):57-65. doi:10.1016/j.cytogfr.2017.03.003.
[12]	梁荣兴, 袁鹏飞, 蔡恒. circTLK1通过调控miR-374a-5p表达对高糖诱导的肾小球系膜细胞损伤的影响[J]. 中国细胞生物学学报, 2021, 43(9):1796-1802.
	LIANG R X, YUAN P F, CAI H. The effect of circTLK1 on the glomerular mesangial cells injury induced by high glucose by regulating the expression of miR-374a-5p[J]. Chinese Journal of Cell Biology, 2021, 43(9):1796-1802. doi:10.11844/cjcb.2021.09.0008.
[13]	林乔轩, 马屹茕, 丁国华. 表观遗传学与糖尿病肾脏病[J]. 中华肾脏病杂志, 2020, 36(1):58-62.
	LIN Q X, MA Y Q, DING G H. Emerging epigenetic mechanisms in diabetic kidney disease[J]. Chinese Journal of Nephrology, 2020, 36(1):58-62. doi:10.3760/cma.j.issn.1001-7097.2020.01.013.
[14]	岳锐, 陈利婷, 王喜悦, 等. DNA甲基化改变与糖尿病肾病发病的相关性研究进展[J]. 国际遗传学杂志, 2022, 45(1):26-30.
	YUE R, CHEN L T, WANG X Y, et al. Study on the relationship between DNA methylation changes and the pathogenesis of diabetic nephropathy[J]. International Journal of Genetics, 2022, 45(1):26-30. doi:10.3760/cma.j.cn231536-20210802-00099.
[15]	ZHANG L, ZHANG Q, LIU S, et al. DNA methyltransferase 1 may be a therapy target for attenuatingdiabetic nephropathy and podocyte injury[J]. Kidney Int, 2017, 92(1):140-153. doi:10.1016/j.kint.2017.01.010.
[16]	CHEN G, CHEN H, REN S, et al. Aberrant DNA methylation of mTOR pathway genes promotes inflammatory activation of immune cells in diabetic kidney disease[J]. Kidney Int, 2019, 96(2):409-420. doi:10.1016/j.kint.2019.02.020.
[17]	GUO X, ZHU Y, SUN Y, et al. IL-6 accelerates renal fibrosis after acute kidney injury via DNMT1-dependent FOXO3a methylation and activation of Wnt/β-catenin pathway[J]. Int Immunopharmacol, 2022, 109:108746. doi:10.1016/j.intimp.2022.108746.
[18]	师晶晶, 侯玉龙, 刘云, 等. 白介素10及DNA甲基转移酶1在糖尿病肾脏疾病患者肾脏组织中的表达及相关性分析[J]. 中国糖尿病杂志, 2019, 27(7):522-527.
	SHI J J, HOU Y L, LIU Y, et al. Expression and correlation analysis of interleukin-10 and DNA methyltransferase 1 in kidney tissue of patients with diabetic kidney disease[J]. Chinese Journal of Diabetes, 2019, 27(7):522-527. doi:10.3969/j.issn.1006-6187.2019.07.009.

组别	n	年龄（岁）	BMI （kg/m²）	性别（男/女）	文化程度（高中及以下/高中以上）	吸烟史（有/无）
对照组	50	52.22±1.31	22.21±1.23	23/27	24/26	27/23
DKD组	150	52.18±1.30	22.23±1.32	71/79	76/74	80/70
t或χ²		0.188	0.094	0.027	0.107	0.007

组别	n	年龄（岁）	BMI （kg/m²）	性别（男/女）	文化程度（高中及以下/高中以上）	吸烟史（有/无）
对照组	50	52.22±1.31	22.21±1.23	23/27	24/26	27/23
DKD组	150	52.18±1.30	22.23±1.32	71/79	76/74	80/70
t或χ²		0.188	0.094	0.027	0.107	0.007

组别	n	空腹血糖（mmol/L）	IL-6 （μg/L）	DNMT1	血肌酐（μmol/L）	eGFR	24 h UAER （mg）	总胆固醇（mmol/L）	三酰甘油（mmol/L）	HDL-C （mmol/L）	LDL-C （mmol/L）	糖化血红蛋白（%）
对照组	50	4.91±0.52	52.23±3.17	0.07±0.02	62.14±10.55	104.89±14.62	5.12±1.62	4.68±0.82	1.83±0.62	1.42±0.24	2.41±0.75	0.67±0.08
DKD组	150	10.80±2.30	70.05±4.01	0.13±0.03	91.74±22.98	80.17±10.82	604.29±107.63	4.42±0.93	2.01±0.83	1.19±0.23	3.61±0.86	9.08±1.12
t		17.928^＊＊	28.571^＊＊	13.188^＊＊	8.793^＊＊	12.749^＊＊	39.297^＊＊	1.761	1.407	6.057^＊＊	8.180^＊＊	52.963^＊＊

组别	n	空腹血糖（mmol/L）	IL-6 （μg/L）	DNMT1	血肌酐（μmol/L）	eGFR	24 h UAER （mg）	总胆固醇（mmol/L）	三酰甘油（mmol/L）	HDL-C （mmol/L）	LDL-C （mmol/L）	糖化血红蛋白（%）
对照组	50	4.91±0.52	52.23±3.17	0.07±0.02	62.14±10.55	104.89±14.62	5.12±1.62	4.68±0.82	1.83±0.62	1.42±0.24	2.41±0.75	0.67±0.08
DKD组	150	10.80±2.30	70.05±4.01	0.13±0.03	91.74±22.98	80.17±10.82	604.29±107.63	4.42±0.93	2.01±0.83	1.19±0.23	3.61±0.86	9.08±1.12
t		17.928^＊＊	28.571^＊＊	13.188^＊＊	8.793^＊＊	12.749^＊＊	39.297^＊＊	1.761	1.407	6.057^＊＊	8.180^＊＊	52.963^＊＊

指标	IL-6		DNMT1
指标	r	P	r	P
空腹血糖	0.166	0.251	0.221	0.124
糖化血红蛋白	0.258	0.176	0.266	0.109
血肌酐	0.303	0.114	0.162	0.318
eGFR	-0.354	0.068	-0.369	0.107
24 h UAER	0.551	<0.001	0.570	<0.001
HDL-C	-0.312	0.107	-0.154	0.325
LDL-C	0.303	0.116	0.267	0.138