Diagnostic value of nucleotide-binding oligomerization domain-like receptor protein 3 inflammatory body and sphingosine-1-phosphate in early diabetic nephropathy and its progression_West China Medical Journal

Authors：

LIN Yan ¹ , LI Jing ¹ , YU Xiangyou ¹ , LIU Lingjiao ¹ , YAN Ni ¹ ,  DUAN Chaoyang ²

1. Department of Endocrinology, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi 710068, P. R. China;
2. Department of Nephrology, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710004, P. R. China;

Corresponding author：

DUAN Chaoyang, Email: duanzhaoyang2005@yeah.net

Keywords：

Nucleotide-binding oligomerization domain-like receptor protein 3 inflammatory body; sphingosine-1-phosphate; diabetic nephropathy; early diabetic nephropathy; diagnostic value

DOI：

10.7507/1002-0179.202108088

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Objective To investigate the diagnostic value of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammatory body and sphingosine-1-phosphate (S1P) in early diabetic nephropathy and its progression. Methods A total of 600 diabetic patients who were treated in Shaanxi Provincial People’s Hospital between January 2018 and December 2020 were selected, and the patients were divided into simple diabetes group, early diabetic nephropathy group and clinical diabetic nephropathy group. The expression of NLRP3 messenger RNA (mRNA) in fasting venous blood mononuclear cells was detected by real-time fluorescence quantitative polymerase chain reaction, and the level of S1P was detected by enzyme-linked immunosorbent assay double-antibody sandwich method. Pearson correlation analysis was used to explore the correlation between blood NLRP3 mRNA and S1P levels. The receiver operating characteristic curve was used to evaluate the diagnostic value of blood NLRP3 mRNA and S1P levels in early diabetic nephropathy and clinical diabetic nephropathy. Results Among the 600 diabetic patients, 205 were in the simple diabetes group, 198 in the early diabetic nephropathy group and 197 in the clinical diabetic nephropathy group. There was no significant difference in age and gender among the three groups (P>0.05). The blood levels of NLRP3 mRNA and S1P in the clinical diabetic nephropathy group were higher than those in the early diabetic nephropathy group and the simple diabetes group, the blood NLRP3 mRNA and S1P levels in the early diabetic nephropathy group were higher than those in the simple diabetes group. The differences were statistically significant, and the blood NLRP3 mRNA levels of the three groups were 2.69±0.64 vs. 2.05±0.56 vs. 1.76±0.51, and the S1P levels were (1.49±0.27) vs. (1.16±0.13) vs. (0.89±0.07) μmol/L (P<0.05). There was a positive correlation between blood NLRP3 mRNA and S1P level in patients (r=0.455, P<0.001). Blood NLRP3 mRNA, S1P levels and their combined detection can be used to diagnose whether diabetic patients develop early diabetic nephropathy (area under the receiver operating characteristic curve were 0.645, 0.968, 0.971; P<0.001) and whether it progressed to clinical diabetic nephropathy (area under the receiver operating characteristic curve were 0.825, 0.918, and 0.945; P<0.001). Conclusion Blood NLRP3 mRNA and S1P levels can be used to diagnose early diabetic nephropathy and evaluate its disease progression.

Citation： LIN Yan, LI Jing, YU Xiangyou, LIU Lingjiao, YAN Ni, DUAN Chaoyang. Diagnostic value of nucleotide-binding oligomerization domain-like receptor protein 3 inflammatory body and sphingosine-1-phosphate in early diabetic nephropathy and its progression. West China Medical Journal, 2022, 37(7): 1035-1040. doi: 10.7507/1002-0179.202108088 Copy

1.	张杜丹, 唐迅, 靳丹瑶, 等. 中国成年人糖尿病患病率 Meta 分析. 中华流行病学杂志, 2018, 39(6): 852-857.
2.	郝玉婷, 林洁, 秦杰. 联合检测标志物在糖尿病肾病早期肾损伤诊断中的临床价值. 西部医学, 2018, 30(10): 1535-1538, 1546.
3.	徐静, 胡晓帆, 黄威, 等. 糖尿病肾病与伴糖尿病的非糖尿病肾脏疾病患者临床病理特征分析. 中华内科杂志, 2017, 56(12): 924-929.
4.	程龙飞, 章金灿, 黄泽伟, 等. 糖化血红蛋白联合尿微量白蛋白检测对糖尿病肾病早期诊断的临床价值. 中华临床医师杂志(电子版), 2016, 10(16): 2382-2385.
5.	Wang S, Li Y, Fan J, et al. Interleukin-22 ameliorated renal injury and fibrosis in diabetic nephropathy through inhibition of NLRP3 inflammasome activation. Cell Death Dis, 2017, 8(7): e2937.
6.	张婧瑶, 刘卫东, 刘函晔, 等. 1-磷酸鞘氨醇与相关疾病的研究进展. 生理科学进展, 2019, 50(3): 200-204.
7.	葛均波, 徐永健, 王辰. 内科学. 9 版. 北京: 人民卫生出版社, 2018: 735-734.
8.	郭思若, 张爱华. 糖尿病肾病的诊断及鉴别诊断. 中华全科医师杂志, 2017, 16(10): 750-752.
9.	Strelitz J, Ahern AL, Long GH, et al. Changes in behaviors after diagnosis of type 2 diabetes and 10-year incidence of cardiovascular disease and mortality. Cardiovasc Diabetol, 2019, 18(1): 98.
10.	杨宏秀, 张会芬, 刘丽, 等. 血清 NGAL、TRF、hs-CRP 及 SF 在糖尿病肾病诊断中的价值. 山东医药, 2017, 57(46): 50-52.
11.	Lu H, Deng S, Zheng M, et al. iTRAQ plasma proteomics analysis for candidate biomarkers of type 2 incipient diabetic nephropathy. Clin Proteomics, 2019, 16: 33.
12.	Feng H, Gu J, Gou F, et al. High glucose and lipopolysaccharide prime NLRP3 inflammasome via ROS/TXNIP pathway in mesangial cells. J Diabetes Res, 2016, 2016: 6973175.
13.	El-Horany HE, Abd-Ellatif RN, Watany M, et al. NLRP3 expression and urinary HSP72 in relation to biomarkers of inflammation and oxidative stress in diabetic nephropathy patients. IUBMB Life, 2017, 69(8): 623-630.
14.	周路平, 黄炜, 徐勇, 等. 甜味受体在糖尿病肾病 NLRP3 炎症信号活化中的作用. 中华内分泌代谢杂志, 2018, 34(7): 587-593.
15.	Zhang C, Boini KM, Xia M, et al. Activation of nod-like receptor protein 3 inflammasomes turns on podocyte injury and glomerular sclerosis in hyperhomocysteinemia. Hypertension, 2012, 60(1): 154-162.
16.	Gao C, Chen J, Fan F, et al. RIPK2-mediated autophagy and negatively regulated ROS-NLRP3 inflammasome signaling in GMCs stimulated with high glucose. Mediators Inflamm, 2019, 2019: 6207563.
17.	Hou Y, Lin S, Qiu J, et al. NLRP3 inflammasome negatively regulates podocyte autophagy in diabetic nephropathy. Biochem Biophys Res Commun, 2020, 521(3): 791-798.
18.	毛海霞, 欧三桃. NLRP3 炎性小体与糖尿病肾病的研究进展. 西南军医, 2021, 23(1): 30-34.
19.	Chen K, Feng L, Hu W, et al. Optineurin inhibits NLRP3 inflammasome activation by enhancing mitophagy of renal tubular cells in diabetic nephropathy. FASEB J, 2019, 33(3): 4571-4585.
20.	Feng H, Zhu X, Tang Y, et al. Astragaloside IV ameliorates diabetic nephropathy in db/db mice by inhibiting NLRP3 inflammasome-mediated inflammation. Int J Mol Med, 2021, 48(2): 164.
21.	Zhang L, Jing M, Liu Q. Crocin alleviates the inflammation and oxidative stress responses associated with diabetic nephropathy in rats via NLRP3 inflammasomes. Life Sci, 2021, 278: 119542.
22.	蒋东波, 张小燕. 糖尿病肾病患者肾脏活检组织中 NLRP3 炎症小体表达水平与肾损害的关系. 热带医学杂志, 2021, 21(1): 99-102, 封 4.
23.	黄秀丽, 吴艳, 王超平, 等. 老年糖尿病肾病患者外周血 NLRP3 炎性体与肾损伤指标的相关性分析. 老年医学与保健, 2017, 23(6): 496-498.
24.	Lan T, Liu W, Xie X, et al. Sphingosine kinase-1 pathway mediates high glucose-induced fibronectin expression in glomerular mesangial cells. Mol Endocrinol, 2011, 25(12): 2094-2105.
25.	Awad AS, Rouse MD, Khutsishvili K, et al. Chronic sphingosine 1-phosphate 1 receptor activation attenuates early-stage diabetic nephropathy independent of lymphocytes. Kidney Int, 2011, 79(10): 1090-1098.
26.	Chen C, Gong W, Li C, et al. Sphingosine kinase 1 mediates AGEs-induced fibronectin upregulation in diabetic nephropathy. Oncotarget, 2017, 8(45): 78660-78676.
27.	El-Shewy HM, Sohn M, Wilson P, et al. Low-density lipoprotein induced expression of connective tissue growth factor via transactivation of sphingosine 1-phosphate receptors in mesangial cells. Mol Endocrinol, 2012, 26(5): 833-845.
28.	李林徽, 张瑾, 尹建红, 等. T 淋巴细胞 CD69 抗原表达水平和 S1P、TGF-β1 等细胞因子在糖尿病肾病中的研究进展. 中西医结合心脑血管病杂志, 2020, 18(4): 590-593.
29.	Bekpinar S, Yenidunya G, Gurdol F, et al. The effect of nephropathy on plasma sphingosine 1-phosphate concentrations in patients with type 2 diabetes. Clin Biochem, 2015, 48(18): 1264-1267.
30.	赵郁松, 马毓敏, 梅笑雪. 血清淋巴管生成因子介导糖尿病肾病进展的相关性. 广西医科大学学报, 2022, 39(1): 127-131.
31.	Imasawa T, Kitamura H, Ohkawa R, et al. Unbalanced expression of sphingosine 1-phosphate receptors in diabetic nephropathy. Exp Toxicol Pathol, 2010, 62(1): 53-60.

1. 张杜丹, 唐迅, 靳丹瑶, 等. 中国成年人糖尿病患病率 Meta 分析. 中华流行病学杂志, 2018, 39(6): 852-857.
2. 郝玉婷, 林洁, 秦杰. 联合检测标志物在糖尿病肾病早期肾损伤诊断中的临床价值. 西部医学, 2018, 30(10): 1535-1538, 1546.
3. 徐静, 胡晓帆, 黄威, 等. 糖尿病肾病与伴糖尿病的非糖尿病肾脏疾病患者临床病理特征分析. 中华内科杂志, 2017, 56(12): 924-929.
4. 程龙飞, 章金灿, 黄泽伟, 等. 糖化血红蛋白联合尿微量白蛋白检测对糖尿病肾病早期诊断的临床价值. 中华临床医师杂志(电子版), 2016, 10(16): 2382-2385.
5. Wang S, Li Y, Fan J, et al. Interleukin-22 ameliorated renal injury and fibrosis in diabetic nephropathy through inhibition of NLRP3 inflammasome activation. Cell Death Dis, 2017, 8(7): e2937.
6. 张婧瑶, 刘卫东, 刘函晔, 等. 1-磷酸鞘氨醇与相关疾病的研究进展. 生理科学进展, 2019, 50(3): 200-204.
7. 葛均波, 徐永健, 王辰. 内科学. 9 版. 北京: 人民卫生出版社, 2018: 735-734.
8. 郭思若, 张爱华. 糖尿病肾病的诊断及鉴别诊断. 中华全科医师杂志, 2017, 16(10): 750-752.
9. Strelitz J, Ahern AL, Long GH, et al. Changes in behaviors after diagnosis of type 2 diabetes and 10-year incidence of cardiovascular disease and mortality. Cardiovasc Diabetol, 2019, 18(1): 98.
10. 杨宏秀, 张会芬, 刘丽, 等. 血清 NGAL、TRF、hs-CRP 及 SF 在糖尿病肾病诊断中的价值. 山东医药, 2017, 57(46): 50-52.
11. Lu H, Deng S, Zheng M, et al. iTRAQ plasma proteomics analysis for candidate biomarkers of type 2 incipient diabetic nephropathy. Clin Proteomics, 2019, 16: 33.
12. Feng H, Gu J, Gou F, et al. High glucose and lipopolysaccharide prime NLRP3 inflammasome via ROS/TXNIP pathway in mesangial cells. J Diabetes Res, 2016, 2016: 6973175.
13. El-Horany HE, Abd-Ellatif RN, Watany M, et al. NLRP3 expression and urinary HSP72 in relation to biomarkers of inflammation and oxidative stress in diabetic nephropathy patients. IUBMB Life, 2017, 69(8): 623-630.
14. 周路平, 黄炜, 徐勇, 等. 甜味受体在糖尿病肾病 NLRP3 炎症信号活化中的作用. 中华内分泌代谢杂志, 2018, 34(7): 587-593.
15. Zhang C, Boini KM, Xia M, et al. Activation of nod-like receptor protein 3 inflammasomes turns on podocyte injury and glomerular sclerosis in hyperhomocysteinemia. Hypertension, 2012, 60(1): 154-162.
16. Gao C, Chen J, Fan F, et al. RIPK2-mediated autophagy and negatively regulated ROS-NLRP3 inflammasome signaling in GMCs stimulated with high glucose. Mediators Inflamm, 2019, 2019: 6207563.
17. Hou Y, Lin S, Qiu J, et al. NLRP3 inflammasome negatively regulates podocyte autophagy in diabetic nephropathy. Biochem Biophys Res Commun, 2020, 521(3): 791-798.
18. 毛海霞, 欧三桃. NLRP3 炎性小体与糖尿病肾病的研究进展. 西南军医, 2021, 23(1): 30-34.
19. Chen K, Feng L, Hu W, et al. Optineurin inhibits NLRP3 inflammasome activation by enhancing mitophagy of renal tubular cells in diabetic nephropathy. FASEB J, 2019, 33(3): 4571-4585.
20. Feng H, Zhu X, Tang Y, et al. Astragaloside IV ameliorates diabetic nephropathy in db/db mice by inhibiting NLRP3 inflammasome-mediated inflammation. Int J Mol Med, 2021, 48(2): 164.
21. Zhang L, Jing M, Liu Q. Crocin alleviates the inflammation and oxidative stress responses associated with diabetic nephropathy in rats via NLRP3 inflammasomes. Life Sci, 2021, 278: 119542.
22. 蒋东波, 张小燕. 糖尿病肾病患者肾脏活检组织中 NLRP3 炎症小体表达水平与肾损害的关系. 热带医学杂志, 2021, 21(1): 99-102, 封 4.
23. 黄秀丽, 吴艳, 王超平, 等. 老年糖尿病肾病患者外周血 NLRP3 炎性体与肾损伤指标的相关性分析. 老年医学与保健, 2017, 23(6): 496-498.
24. Lan T, Liu W, Xie X, et al. Sphingosine kinase-1 pathway mediates high glucose-induced fibronectin expression in glomerular mesangial cells. Mol Endocrinol, 2011, 25(12): 2094-2105.
25. Awad AS, Rouse MD, Khutsishvili K, et al. Chronic sphingosine 1-phosphate 1 receptor activation attenuates early-stage diabetic nephropathy independent of lymphocytes. Kidney Int, 2011, 79(10): 1090-1098.
26. Chen C, Gong W, Li C, et al. Sphingosine kinase 1 mediates AGEs-induced fibronectin upregulation in diabetic nephropathy. Oncotarget, 2017, 8(45): 78660-78676.
27. El-Shewy HM, Sohn M, Wilson P, et al. Low-density lipoprotein induced expression of connective tissue growth factor via transactivation of sphingosine 1-phosphate receptors in mesangial cells. Mol Endocrinol, 2012, 26(5): 833-845.
28. 李林徽, 张瑾, 尹建红, 等. T 淋巴细胞 CD69 抗原表达水平和 S1P、TGF-β1 等细胞因子在糖尿病肾病中的研究进展. 中西医结合心脑血管病杂志, 2020, 18(4): 590-593.
29. Bekpinar S, Yenidunya G, Gurdol F, et al. The effect of nephropathy on plasma sphingosine 1-phosphate concentrations in patients with type 2 diabetes. Clin Biochem, 2015, 48(18): 1264-1267.
30. 赵郁松, 马毓敏, 梅笑雪. 血清淋巴管生成因子介导糖尿病肾病进展的相关性. 广西医科大学学报, 2022, 39(1): 127-131.
31. Imasawa T, Kitamura H, Ohkawa R, et al. Unbalanced expression of sphingosine 1-phosphate receptors in diabetic nephropathy. Exp Toxicol Pathol, 2010, 62(1): 53-60.

West China Medical Journal

Diagnostic value of nucleotide-binding oligomerization domain-like receptor protein 3 inflammatory body and sphingosine-1-phosphate in early diabetic nephropathy and its progression

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