| Citation: |
HE Yiqian, XIE Jun, ZHAO Bingjia, LIANG Xiaochun, QU Ling. Protective Effect and Molecular Mechanism of Hirudin on Kidney of Diabetic Rats[J]. Medical Journal of Peking Union Medical College Hospital, 2024, 15(6): 1372-1381. DOI: 10.12290/xhyxzz.2024-0366
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To investigate the protective effect of hirudin on kidneys of diabetic rats and its molecular mechanism.
Eighteen Sprague-Dawley rats were randomly divided into control group (n=5) and model group (n=13). The model group was injected intraperitoneally with streptozotocin(STZ) to establish a diabetic rat model. Eight weeks after STZ injection, successfully modeled diabetic rats were randomly divided into diabetic model group (n=6, with 1 rat dead due to hyperglycemia) and hirudin treatment group (n=5). The hirudin treatment group was administered 5 U hirudin while the control group and diabetic model group were injected subcutaneously with equal volume of phosphate buffered saline once daily for six weeks. During the experiment, the rats' body weight and random blood glucose levels were monitored every two weeks. After 6 weeks of treatment, renal function parameters were measured, and the levels of tumor necrosis factor α (TNF-α), transforming growth factor β1 (TGF-β1), interleukin 6 (IL-6), fibronectin (FN), nephrin, collagen-Ⅳ (COL-Ⅳ), and proteins related to the Janus kinase 2 (JAK2)/signal transduction and transcriptional activator 3 (STAT3) signaling pathway were assessed. Renal histopathological changes were also observed.
Compared with the control group, the diabetic model group showed significantly elevated random blood glucose and renal function parameters during the 6-week treatment (both P < 0.05), along with a significant decrease in body weight(P < 0.05) and renal pathological damage. Compared with the diabetic model group, the renal function parameters of hirudin treatment group were significantly decreased (P < 0.05), the renal pathological damage was ameliorated. Compared with the control group, the expression levels of FN, COL-Ⅳ, TNF-α, TGF-β1, IL-6, p-JAK2, and p-STAT3 in the kidneys of diabetic model group were significantly increased (all P < 0.05), while the expression of nephrin was reduced (P < 0.05). Compared with the diabetic group, the expression level of FN, COL-Ⅳ, TNF-α, TGF-β1, IL-6, p-JAK2, and p-STAT3 in hirudin treatment group were significantly reduced (all P < 0.05), while the nephrin expression increased (P < 0.05).
Hirudin improved renal pathological changes in diabetic rats, and its mechanism may be related to the decrease of fibrosis-related factors and inhibition of the activation of the JAK2/STAT3 pathway.
| [1] |
International Diabetes Federation. IDF 1040 Atlas Diabetes and Kidney Disease Report V4[EB/OL]. [2023-10-01]. https://diabetesatlas.org/.
|
| [2] |
Umanath K, Lewis J B. Update on diabetic nephropathy: core curriculum 2018[J]. Am J Kidney Dis, 2018, 71(6): 884-895. DOI: 10.1053/j.ajkd.2017.10.026
|
| [3] |
Alicic R Z, Rooney M T, Tuttle K R. Diabetic kidney disease: challenges, progress, and possibilities[J]. Clin J Am Soc Nephrol, 2017, 12(12): 2032-2045. DOI: 10.2215/CJN.11491116
|
| [4] |
Selby N M, Taal M W. An updated overview of diabetic nephropathy: Diagnosis, prognosis, treatment goals and latest guidelines[J]. Diabetes Obes Metab, 2020, 22(S1): 3-15. DOI: 10.1111/dom.14007
|
| [5] |
Feng L X, Chen C, Xiong X, et al. PS-MPs promotes the progression of inflammation and fibrosis in diabetic nephropathy through NLRP3/Caspase-1 and TGF-β1/Smad2/3 signaling pathways[J]. Ecotoxicol Environ Saf, 2024, 273: 116102. DOI: 10.1016/j.ecoenv.2024.116102
|
| [6] |
Bhattacharjee N, Barma S, Konwar N, et al. Mechanistic insight of diabetic nephropathy and its pharmacotherapeutic targets: an update[J]. Eur J Pharmacol, 2016, 791: 8-24. DOI: 10.1016/j.ejphar.2016.08.022
|
| [7] |
Brosius F C, Tuttle K R, Kretzler M. JAK inhibition in the treatment of diabetic kidney disease[J]. Diabetologia, 2016, 59(8): 1624-1627. DOI: 10.1007/s00125-016-4021-5
|
| [8] |
Chen Y, Chen L, Yang T W. Silymarin nanoliposomes attenuate renal injury on diabetic nephropathy rats via co-suppressing TGF-β/Smad and JAK2/STAT3/SOCS1 pathway[J]. Life Sci, 2021, 271: 119197. DOI: 10.1016/j.lfs.2021.119197
|
| [9] |
Gao C, Fei X, Wang M, et al. Cardamomin protects from diabetes-induced kidney damage through modulating PI3K/AKT and JAK/STAT signaling pathways in rats[J]. Int Immunopharmacol, 2022, 107: 108610. DOI: 10.1016/j.intimp.2022.108610
|
| [10] |
Huang J S, Lee Y H, Chuang L Y, et al. Cinnamaldehyde and nitric oxide attenuate advanced glycation end products-induced the Jak/STAT signaling in human renal tubular cells[J]. J Cell Biochem, 2015, 116(6): 1028-1038. DOI: 10.1002/jcb.25058
|
| [11] |
Zaghloul R A, Abdelghany A M, Samra Y A. Rutin and selenium nanoparticles protected against STZ-induced diabetic nephropathy in rats through downregulating Jak-2/Stat3 pathway and upregulating Nrf-2/HO-1 pathway[J]. Eur J Pharmacol, 2022, 933: 175289. DOI: 10.1016/j.ejphar.2022.175289
|
| [12] |
Zheng C, Huang L, Luo W, et al. Inhibition of STAT3 in tubular epithelial cells prevents kidney fibrosis and nephropathy in STZ-induced diabetic mice[J]. Cell Death Dis, 2019, 10(11): 848. DOI: 10.1038/s41419-019-2085-0
|
| [13] |
Lu T C, Wang Z H, Feng X B, et al. Knockdown of Stat3 activity in vivo prevents diabetic glomerulopathy[J]. Kidney Int, 2009, 76(1): 63-71. DOI: 10.1038/ki.2009.98
|
| [14] |
Junren C, Xiaofang X, Huiqiong Z, et al. Pharmacological activities and mechanisms of hirudin and its derivatives-a review[J]. Front Pharmacol, 2021, 12: 660757. DOI: 10.3389/fphar.2021.660757
|
| [15] |
Shi Y, Liang X C, Zhang H, et al. Combination of quercetin, cinnamaldehyde and hirudin protects rat dorsal root ganglion neurons against high glucose-induced injury through Nrf-2/HO-1 activation and NF-κB inhibition[J]. Chin J Integr Med, 2017, 23(9): 663-671. DOI: 10.1007/s11655-017-2405-0
|
| [16] |
刘頔. ERK信号通路在高糖诱导的髓鞘化损伤中的作用及槲皮素、桂皮醛、水蛭素和单体组合对其影响的研究[D]. 北京: 北京协和医学院, 2016.
Liu D. The mechanism of ERK pathway in high glucose induced myelination impairment and the protective effects of quercetin, hirudin, cinnamaldehyde and the combinations of them[D]. Beijing: Peking Union Medical College, 2016.
|
| [17] |
Liu D, Liang X C, Sun Y, et al. Combination of quercetin, hirudin and cinnamaldehyde promotes Schwann cell differentiation and myelination against high glucose by inhibiting ERK signaling pathway[J]. Chin J Integr Med, 2020, 26(8): 591-598. DOI: 10.1007/s11655-020-2721-7
|
| [18] |
Pang X X, Zhang Y G, Peng Z N, et al. Hirudin reduces nephropathy microangiopathy in STZ-induced diabetes rats by inhibiting endothelial cell migration and angiogenesis[J]. Life Sci, 2020, 255: 117779. DOI: 10.1016/j.lfs.2020.117779
|
| [19] |
Han J R, Pang X X, Zhang Y G, et al. Hirudin protects against kidney damage in streptozotocin-induced diabetic nephropathy rats by inhibiting inflammation via P38 MAPK/NF-κB pathway[J]. Drug Des Devel Ther, 2020, 14: 3223-3234. DOI: 10.2147/DDDT.S257613
|
| [20] |
Long C L, Lin Q, Mo J L, et al. Hirudin attenuates puromycin aminonucleoside-induced glomerular podocyte injury by inhibiting MAPK-mediated endoplasmic reticulum stress[J]. Drug Dev Res, 2022, 83(4): 1047-1056. DOI: 10.1002/ddr.21932
|
| [21] |
Noshahr Z S, Salmani H, Khajavi Rad A, et al. Animal models of diabetes-associated renal injury[J]. J Diabetes Res, 2020, 2020: 9416419.
|
| [22] |
中华中医药学会, 北京中医药大学东直门医院, 北京中医药大学. 糖尿病肾脏疾病中西医结合诊疗指南[J]. 北京中医药大学学报, 2024, 47(4): 580-592. DOI: 10.3969/j.issn.1006-2157.2024.04.005
China Association of Chinese Medicine, Beijing University of Traditional Chinese Medicine Dongzhimen Hospital, Beijing University of Chinese Medicine. Diagnosis and treatment guideline of integrated traditional Chinese and western medicine for diabetic kidney disease[J]. J Beijing Univ Tradit Chin Med, 2024, 47(4): 580-592. DOI: 10.3969/j.issn.1006-2157.2024.04.005
|
| [23] |
柳志诚, 方永晟, 杨国华, 等. 水蛭素的药理作用研究进展[J]. 中国医药科学, 2022, 12(21): 56-59. DOI: 10.3969/j.issn.2095-0616.2022.21.015
Liu Z C, Fang Y S, Yang G H, et al. Research progress on pharmacological effects of hirudin[J]. China Med Pharm, 2022, 12(21): 56-59. DOI: 10.3969/j.issn.2095-0616.2022.21.015
|
| [24] |
Fan M L, Lan X T, Wang Q L, et al. Renal function protection and the mechanism of ginsenosides: current progress and future perspectives[J]. Front Pharmacol, 2023, 14: 1070738. DOI: 10.3389/fphar.2023.1070738
|
| [25] |
Cao Y L, Lin J H, Hammes H P, et al. Cellular phenotypic transitions in diabetic nephropathy: An update[J]. Front Pharmacol, 2022, 13: 1038073. DOI: 10.3389/fphar.2022.1038073
|
| [26] |
Chen F, Zhu X G, Sun Z Q, et al. Astilbin inhibits high glucose-induced inflammation and extracellular matrix accumulation by suppressing the TLR4/MyD88/NF-κB pathway in rat glomerular mesangial cells[J]. Front Pharmacol, 2018, 9: 1187. DOI: 10.3389/fphar.2018.01187
|
| [27] |
Zhu X G, Shi J, Li H C. Liquiritigenin attenuates high glucose-induced mesangial matrix accumulation, oxidative stress, and inflammation by suppression of the NF-κB and NLRP3 inflammasome pathways[J]. Biomed Pharmacother, 2018, 106: 976-982. DOI: 10.1016/j.biopha.2018.07.045
|
| [28] |
Chen Q, Tao J, Li G P, et al. Astaxanthin ameliorates experimental diabetes-induced renal oxidative stress and fibronectin by upregulating connexin43 in glomerular mesangial cells and diabetic mice[J]. Eur J Pharmacol, 2018, 840: 33-43. DOI: 10.1016/j.ejphar.2018.09.028
|
| [29] |
Lennon R, Randles M J, Humphries M J. The importance of podocyte adhesion for a healthy glomerulus[J]. Front Endocrinol (Lausanne), 2014, 5: 160.
|
| [30] |
Li Y M, Liu J P, Liao G N, et al. Early intervention with mesenchymal stem cells prevents nephropathy in diabetic rats by ameliorating the inflammatory microenvironment[J]. Int J Mol Med, 2018, 41(5): 2629-2639.
|
| [31] |
El-Kady M M, Naggar R A, Guimei M, et al. Early renoprotective effect of ruxolitinib in a rat model of diabetic nephro-pathy[J]. Pharmaceuticals (Basel), 2021, 14(7): 608. DOI: 10.3390/ph14070608
|
| [32] |
Wu H M, Xu F, Huang X L, et al. Lupenone improves type 2 diabetic nephropathy by regulating NF-κB pathway-mediated inflammation and TGF-β1/Smad/CTGF-associated fibrosis[J]. Phytomedicine, 2023, 118: 154959. DOI: 10.1016/j.phymed.2023.154959
|
| [33] |
Shen Y L, Jiang Y P, Li X Q, et al. Corrigendum: ErHuang formula improves renal fibrosis in diabetic nephropathy rats by inhibiting CXCL6/JAK/STAT3 signaling pathway[J]. Front Pharmacol, 2021, 12: 789192. DOI: 10.3389/fphar.2021.789192
|
| [34] |
Shi Y H, Zhao S, Wang C, et al. Fluvastatin inhibits activation of JAK and STAT proteins in diabetic rat glomeruli and mesangial cells under high glucose conditions[J]. Acta Pharmacol Sin, 2007, 28(12): 1938-1946. DOI: 10.1111/j.1745-7254.2007.00653.x
|
| [35] |
Li Y X, Zhao J, Yin Y, et al. The role of IL-6 in fibrotic diseases: molecular and cellular mechanisms[J]. Int J Biol Sci, 2022, 18(14): 5405-5414. DOI: 10.7150/ijbs.75876
|
| [36] |
Ortiz-Muñoz G, Lopez-Parra V, Lopez-Franco O, et al. Suppressors of cytokine signaling abrogate diabetic nephropathy[J]. J Am Soc Nephrol, 2010, 21(5): 763-772. DOI: 10.1681/ASN.2009060625
|
| [37] |
李莹, 崔丽. 水蛭素药物治疗尿微量白蛋白为主要表现的糖尿病肾病和高血压肾病的临床研究[J]. 临床合理用药杂志, 2010, 3(22): 6-7.
Li Y, Cui L. Clinical study on hirudin in diabetic nephropathy with umalb as the main manifestations and hypertension kidney disease[J]. Chin J Clin Ration Drug Use, 2010, 3(22): 6-7.
|
| [38] |
于丹丹, 章轶立, 谢雁鸣, 等. 基于倾向性评分法的脉血康胶囊治疗肾病的临床用药有效性研究[J]. 辽宁中医杂志, 2019, 46(11): 2265-2269.
Yu D D, Zhang Y L, Xie Y M, et al. Propensity score-based study on effectiveness of clinical drugs for treating kidney disease with Maixuekang capsule[J]. Liaoning J Tradit Chin Med, 2019, 46(11): 2265-2269.
|
| [39] |
刘蒙蒙, 陈学勋, 秦萍, 等. 脉血康胶囊对特发性膜性肾病患者血栓弹力图影响及其疗效观察[J]. 中成药, 2016, 38(4): 751-755.
Liu M M, Chen X X, Qin P, et al. Effect of maixuekang capsules on thrombelastography in patients with idiopathic membranous nephropathy and clinical observation[J]. Chin Tradit Pat Med, 2016, 38(4): 751-755.
|
| [40] |
刘吉尧, 徐霜霜, 曾海文, 等. 水蛭对糖尿病肾病的疗效及安全性的Meta分析[J]. 实用中医内科杂志, 2021, 35(5): 137-139.
Liu J Y, Xu S S, Zeng H W, et al. Meta-analysis of efficacy and safety of leech on diabetic nephropathy[J]. J Pract Tradit Chin Intern Med, 2021, 35(5): 137-139.
|
| [41] |
van Es N, Bleker S M, Büller H R, et al. New developments in parenteral anticoagulation for arterial and venous thromboembolism[J]. Best Pract Res Clin Haematol, 2013, 26(2): 203-213. DOI: 10.1016/j.beha.2013.07.010
|
| [42] |
王朝, 蒋莉莉, 施莉莉, 等. 水蛭配合西药治疗糖尿病肾病及对尿微量白蛋白和内皮功能的影响[J]. 陕西中医, 2014, 35(10): 1306-1307. DOI: 10.3969/j.issn.1000-7369.2014.10.016
Wang C, Jiang L L, Shi L L, et al. Effect of hirudo combined with western medicine on diabetes nephropathy and urinary microalbumin and endothelial function[J]. Shaanxi J Tradit Chin Med, 2014, 35(10): 1306-1307. DOI: 10.3969/j.issn.1000-7369.2014.10.016
|
| [43] |
Dong X N, Meng Z Y, Jin J D, et al. Development, validation, and clinical pharmacokinetic application of ultra-performance liquid chromatography/tandem mass spectrometry method for simultaneously determining a novel recombinant hirudin derivative (Neorudin) and its active metabolite in human serum[J]. J Chromatogr B Analyt Technol Biomed Life Sci, 2017, 1063: 204-213. DOI: 10.1016/j.jchromb.2017.08.030
|
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