药学学报, 2019, 54(8): 1356-1363
王钦汶, 戴新新, 项想, 宿树兰, 郭建明, 朱悦, 钱大玮, 段金廒. 丹酚酸和丹参酮干预糖尿病肾病的分子机制研究进展[J]. 药学学报, 2019, 54(8): 1356-1363.
WANG Qin-wen, DAI Xin-xin, XIANG Xiang, SU Shu-lan, GUO Jian-ming, ZHU Yue, QIAN Da-wei, DUAN Jin-ao. Advances in the molecular mechanism of salvianolic acid and tanshinone for intervention of diabetic kidney disease[J]. Acta Pharmaceutica Sinica, 2019, 54(8): 1356-1363.

王钦汶, 戴新新, 项想, 宿树兰, 郭建明, 朱悦, 钱大玮, 段金廒
南京中医药大学, 江苏省中药资源产业化过程协同创新中心, 中药资源产业化与方剂创新药物国家地方联合工程研究中心, 国家中医药管理局中药资源循环利用重点研究室, 江苏 南京 210023
糖尿病肾病(diabetic kidney disease,DKD)是糖尿病患者最为严重的微血管并发症,也是终末期肾病的主要原因。由于代谢和血流动力学等因素之间的相互作用,激活了导致糖尿病肾脏损伤的常见途径。研究表明,丹参酚酸可通过调节肾小管间质激活素A、转化生长因子-β1和单核细胞趋化蛋白-1来减轻肾纤维化,缓解糖尿病引起的肾损伤;还可通过对蛋白激酶ERK1/2蛋白表达的影响,参与肾小球细胞外基质的重新构建,对糖尿病肾脏具有较好的保护作用。丹参酮可抑制氧化应激介导葡萄糖诱导的肾损伤、抑制蛋白酪氨酸磷酸酶1B(protein-tyrosinephosphatase 1B,PTP1B)活性的表达、改善2型糖尿病患者中胰岛β细胞分泌功能;可通过阻断TGF-β/Smad和NF-κB信号通路、Wnt/β-catenin信号通路,减轻糖尿病肾病的肾间质纤维化。提示丹参酚酸和丹参酮类成分具有明确的防治糖尿病肾病的作用,为丹参酚酸、丹参酮类成分的深入研究与开发提供科学依据和重要支撑。
关键词:    糖尿病肾病      丹参酚酸      丹参酮      分子机制     
Advances in the molecular mechanism of salvianolic acid and tanshinone for intervention of diabetic kidney disease
WANG Qin-wen, DAI Xin-xin, XIANG Xiang, SU Shu-lan, GUO Jian-ming, ZHU Yue, QIAN Da-wei, DUAN Jin-ao
Nanjing University of Traditional Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, State Administration of Traditional Chinese Medicine, Traditional Chinese Medicine Resource Recycling, Nanjing 210023, China
Diabetic kidney disease (DKD) is one of the most serious microvascular complications in diabetic patients, and is the leading cause of end-stage renal disease. The interaction between metabolic and hemodynamic factors leads to activation of the common pathways of diabetic kidney injury. Studies have shown that salvianolic acid can alleviate renal fibrosis and renal injury caused by diabetes by regulating renal tubular interstitial activator A, transforming growth factor-β1 and monocyte chemokine protein-1. It can also participate in the reconstruction of the glomerular extracellular matrix by affecting the expression of protein kinase ERK1/2 protein, which serves a protective effect on diabetic kidneys. Tanshinone can inhibit oxidative stress mediated glucose-induced kidney injury, inhibit the expression of protein tyrosine phosphatase 1B (PTP1B) activity, and improve the secretion function of beta cells in type 2 diabetes mellitus. Interstitial fibrosis in diabetic nephropathy can be alleviated by blocking TGF-β/Smad, NF-κB and Wnt/β-catenin signaling pathway. It has been suggested that salvianolic acid and salvianone are excellent candidates for prevention and treatment of diabetic nephropathy. We provide here the scientific basis for in-depth research and development of salvianolic acid and salvianone into drugs.
Key words:    diabetic kidney disease    salvianolic acid    tanshinone    molecular mechanisms of pharmacological action   
收稿日期: 2018-11-19
DOI: 10.16438/j.0513-4870.2018-1044
基金项目: 国家自然科学基金资助项目(81673533).
通讯作者: 宿树兰,Tel:13809043258,E-mail:sushulan@njucm.edu.cn;段金廒,Tel:86-25-85811291,E-mail:dja@njucm.edu.cn
Email: sushulan@njucm.edu.cn;dja@njucm.edu.cn
PDF(485KB) Free
郭宗儒  在本刊中的所有文章
王钦汶  在本刊中的所有文章
戴新新  在本刊中的所有文章
项想  在本刊中的所有文章
宿树兰  在本刊中的所有文章
郭建明  在本刊中的所有文章
朱悦  在本刊中的所有文章
钱大玮  在本刊中的所有文章
段金廒  在本刊中的所有文章

[1] Stenvinkel P. Chronic kidney disease:a public health priority and harbinger of premature cardiovascular disease[J]. J Intern Med, 2010, 268:456-467.
[2] Dai XX, Su SL, Guo S, et al. Research progress on biological activity and application development of tanshinones[J]. Chin Tradit Herb Drugs (中草药), 2017, 48:1442-1448.
[3] Cai HD. Study on Improvement Effect and Mechanism of Salvia Miltiorrhiza Stem-Leaf on Chronic Renal Function Injury (丹参茎叶对慢性肾功呢损伤的改善作用及机制研究)[D]. Nanjing:Nanjing University of Chinese Medicine (南京中医药大学), 2017.
[4] Krolewski AS, Poznik GD, Placha G, et al. A genome-wide linkage scan for genes controlling variation in urinary albumin excretion in type Ⅱ diabetes[J]. Kidney Int, 2006, 69:129-136.
[5] Vardarli I, Robert L, Hanson RL, et al. Gene for susceptibility to diabetic nephropathy in type 2 diabetes maps to 18q22.3-23[J]. Kidney Int, 2002, 62:2176-2183.
[6] Arsov S, Graf R, van Oeveren W, et al. Advanced glycation endproducts and skin autofluorescence in end stage renal disease:a review[J]. Clin Chem Lab Med, 2014, 52:11.
[7] Prasad K, Tiwari S. Therapeutic interventions for advanced glycation-end products and its receptor-mediated cardiovascular disease[J]. Curr Pharm Des, 2017, 23:937-943.
[8] Yamagishi S, Matusui T. Role of ligand of receptor for advanced glycation end products (RAGE) in peripheral artery disease[J]. Rejuvenation Res, 2018, 21:456-463.
[9] Liu F, Fu Y, Wei C, et al. The expression of GPR109A, NF-κB and IL-1β in peripheral blood leukocytes from patients with type 2 diabetes[J]. Ann Clin Lab Sci, 2014, 44:443-448.
[10] Saulnier PJ, Wheelock KM, Howell S, et al. Advanced glycation end-products predict loss of renal function and correlate with lesions of diabetic kidney disease in American Indians with type 2 diabetes[J]. Diabetes, 2016, 65:3744-3753.
[11] Ren X, Ren L, Wei Q, et al. Advanced glycation end-products decreases expression of endothelial nitric oxide synthase through oxidative stress in human coronary artery endothelial cell[J]. Catdiovasc Diabetol, 2017, 16:52.
[12] Zhao PM, Wang JQ, Ling YJ. Role of endothelial cells injury in the pathogenesis of diabetic nephropathy[J]. Chin J Diabetes (中国糖尿病杂志), 2016, 24:669-672.
[13] Niu S, Bian Z, Tremblay A, et al. Broad infiltration of macrophages leads to a proinflammatory state in streptozotocin-induced hyperglycemic mice[J]. J Immunol, 2016, 197:3293-3301.
[14] Stief T. Glucose initially inhibits and later stimulates blood ROS generation[J]. J Diabetes Mellitus, 2013, 3:5-21.
[15] Flemming NB, Gallo LA, Forbes JM. Mitochondrial dysfunction and sign in diabetic kidney disease:oxidative stress and beyond[J]. Semin Nephrol, 2018, 38:101-110.
[16] Giacco F, Brownlee M. Oxidative stress and diabetic complications[J]. Circ Res, 2010, 107:1058-1070.
[17] Gorin Y, Block K. Nox4 and diabetic nephropathy:with a friend like this, who needs enemies?[J]. Free Radic Biol Med, 2013,61:130-132.
[18] Yao M, Gao F, Wang X, et al. Nox4 is involved in high glucoseinduced apoptosis in renal tubular epithelial cells via Notch pathway[J]. Mol Med Rep, 2017, 15:4319-4325.
[19] Sagoo MK, Gnudi L. Diabetic nephropathy:is there a role for oxidative stress?[J]. Free Radic Biol Med, 2018, 20:50-63.
[20] Navarrogonzález JF, Morafernández C, Murosd FM, et al. Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy[J]. Nat Rev Nephrol, 2011, 7:327-340.
[21] Chen JS, Lee HS, Jin JS, et al. Attenuation of mouse mesangial cell contractility by high glucose and mannitol:involvement of protein kinase C and focal adhesion kinase[J]. J Biomed Sci, 2004, 11:142-151.
[22] Wang S, Li Y, Fan J, et al. Interleukin-22 ameliorated renal injury and fibrosis in diabetic nephropathy through inhibition of NLRP3 inflammasome activation[J]. Cell Death Dis, 2017, 8:e2937.
[23] Liu JF, Liu SY, Zhao ZG, et al. The role of the renin-angiotensinaldehyde sterol system in the pathogenesis of nephropathy[J]. Chin J Gerontol (中国老年学杂志), 2017, 37:2327-2331.
[24] Yang KK, Mou XJ, Shen J, et al. Renin-angiotensin system blockade in correction of glucose metabolic disturbance in uninephrectomized rats[J]. Acad J Second Mil Med Univ (第二军医大学学报), 2015, 36:761-766.
[25] Yang KK. Remnant Kidney Impairments and Metabolic Disorders Induced by Rennin-angiotensin System (肾素-血管紧张素系统介导的残留肾改变和代谢异常)[D]. Guilin:Guilin Medical University (桂林医学院), 2015.
[26] Burns KD. Angiotensin Ⅱ and its receptors in the diabetic kidney[J]. Am J Kidney Dis, 2000, 36:449-467.
[27] Ruiz-Ortega M, Ruperez M, Lorenzo O, et al. Angiotensin Ⅱ regulates the synthesis of proinflammatory cytokines and chemokines in the kidney[J]. Kidney Int, 2002, 62:S12-S22.
[28] O'Donnell MP. The genetic information nondiscrimination Act-A wake-up call:great intentions, but a setback for health impact and cost-effectiveness of workplace health promotion[J]. Am J Health Promot, 2010, 24:4-5.
[29] Chen XX. Inhibitory Effects of Activin A on the Proliferation of Neuro-2a Cells and Its Mechanism (激活素A对Neuro-2a细胞增殖抑制作用及其机制)[D]. Jinlin:Jinlin University (吉林大学), 2018.
[30] Mamin A, Philippe J. Activin A decreases glucagon and arx gene expression in alpha cell lines[J]. Mol Endocrinol, 2007, 21:259-273.
[31] Ueland T, Aukrust P, Aakhus S, et al. Activin A and cardiovascular disease in type 2 diabetes mellitus[J]. Diab Vasc Dis Res, 2012, 9:234-237.
[32] Wang L, Wu QF. Effects of Danshen polyphenolic acid on expression of activin A of kidney tube interstitial in type 2 diabetic nephropathy rats[J]. Global Tradit Chin Med (环球中医药), 2017, 10:1312-1317.
[33] Xu Y. Protective effect of salvianolic acid injection on diabetic nephropathy and its effects on TGF-β-1 and MCP-1[J]. Mod J Integr Tradit Chin Western Med (现代中西医结合杂志), 2014, 23:2083-2084.
[34] Wang Q, Wu X, Cao Z, et al. The effects of tanshinone ⅡA on oxidative stress of kidneys of rats with diabetic nephropathy[J]. Chin J Clin (中华临床医师杂志), 2015, 9:1149-1151.
[35] Wu X, Liu L, Xie H, et al. Tanshinone ⅡA prevents uric acid nephropathy in rats through NF-κB inhibition[J]. Planta Med, 2012, 78:866-873.
[36] Yuan Z, Chen Z, Li QB, et al. Advances in research of protein tyrosine phosphatase 1B and its inhibitors[J]. J China Pharm Univ (中国药科大学学报), 2018, 49:1-9.
[37] Kim DH, Paudel P, Yu T, et al. Characterization of the inhibitory activity of natural tanshinones from Salvia miltiorrhiza roots on protein tyrosine phosphatase 1B[J]. Chem Biol Interact, 2017, 276:65-73.
[38] Wang LH, Wu GL, Lin J, et al. Effect of mitogen-activated protein kinase phosophatase-1 in extracellular matrix reconstruction of renal tissues in rats with diabetes mellitus[J]. Med Pharm J Chin PLA (解放军医药杂志), 2018, 30:9-14.
[39] Wang L, Wu QF. Effects of salvianolic acid on exoression of extracellular ERK1/2 in diabetic nephropathy rats[J]. Chin J Tradit Med Sci Technol (中国中医药科技), 2018, 25:197-201.
[40] Lin X, Zha Y, Zeng XZ, et al. Role of the Wnt/β-catenin signaling pathway in inducing apoptosis and renal fibrosis in 5/6-nephrectomized rats[J]. Mol Med Rep, 2017, 15:3575-3582.
[41] Chen GY, Tang SF, Su BL, et al. Effect of tanshinone ⅡA on renal tumor growth factor-beta 1 and nuclear factor-kappa B in diabetic nephropathy rats[J]. J Guangzhou Univ Tradit Chin Med (广州中医药大学学报), 2015, 32:891-895, 974.
[42] Zhou RB, Liu MH, He HX. Protective effect of sulfotanshinone sodium injection on diabetic rat kidney[J]. China Pharm (中国药业), 2008, 17:7-8.
[43] Tang J, Zhan C, Zhou J. Effects of tanshinone ⅡA on transforming growth factor beta1-Smads signal pathway in renal interstitial fibroblasts of rats[J]. J Huazhong Univ Technolog Med Sci, 2008, 28:539-542.
[44] Liu S, Xi Y, Bettaieb A, et al. Disruption of protein tyrosine phosphatase 1B expression in the pancreas affects β-cell function[J]. Endocrinology, 2014, 155:3329-3338.
[45] Yigitturk G, Acara AC, Erbas O, et al. The antioxidant role of agomelatine and gallic acid on oxidative stress in STZ induced type I diabetic rat testes[J]. J Cardiovasc Pharmacol, 2015, 66:584-592.
[46] Phillips AO, Steadman R. Diabetic nephropathy:the central role of renal proximal tubular cells in tubulointerstitial injury[J]. Histol Histopathol, 2002, 17:247-252.
[47] Phillips AO. The role of renal proximal tubular cells in diabetic nephropathy[J]. Curr Diabetes Rep, 2003, 3:491-496.
[48] Javelaud D, van Kempen L, Alexaki VI, et al. Efficient TGFbeta/Smad signaling in human melanoma cells associated with high c-SKI/SnoN expression[J]. Mol Cancer, 2011, 10:2.
[49] Liu Y, Quan Y. Relationship between inflammatory microenvironment and epithelial-mesenchymal transition and its significance in pancreatic carcinoma[J]. Chin J Clin Res (中国临床研究), 2018, 31:1619-1623.
[50] Brembeck FH, Rosario M, Birchmeier W. Balancing cell adhesion and Wnt signaling, the key role of beta-catenin[J]. Curr Opin Genet Dev, 2006, 16:51-59.
[51] He W, Dai C, Li Y, et al. Wnt/beta-catenin signaling promotes renal interstitial fibrosis[J]. J Am Soc Nephrol, 2009, 20:765-776.
[52] Song JY, Luo HM, Li CF, et al. Salvia miltiorrhiza as medicinal model plant[J]. Acta Pharm Sin (药学学报), 2013, 48:1099-1106.