Effect of Eucommia ulmoides leaves on hyperuricemia and kidney injury induced by a high-fat/high-fructose diet in rats

Document Type : Original Article


1 Henan University of Chinese Medicine, Henan Zhengzhou 450046, China

2 Engineering Technology Research Center for Comprehensive Development and Utilization of Authentic Medicinal Materials from Henan, Henan Zhengzhou 450046, China

3 The Second Affiliated Hospital of Zhengzhou University, Henan Zhengzhou,450014, China

4 Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China

5 Henan Zhongjing Key Laboratory of Prescription, Henan Zhengzhou 450046, China


Objective(s): To investigate the protective and preventive treatment effects of Eucommia ulmoides leaves on a rat model of high-fat and high-fructose diet (HFFD) induced hyperuricemia and renal injury.
Materials and Methods: Network pharmacology and molecular-docking methods were used to predict the effects and action mechanisms of the major components of E. ulmoides leaves on hyperuricemia. Combining literature collection, we used SciFinder and the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and Analysis Platform to collect E. ulmoides leaf flavonoid and iridoid components. Swiss Target Prediction, Similarity ensemble approach (SEA), GeneCards, and the Online Mendelian Inheritance in Man (OMIM) database were used to obtain core targets, and the Search Tool for Recurring Instances of Neighbouring Genes (STRING) protein database was used as core target for gene ontology enrichment Set and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Molecular docking was applied to predict the pathways regulating the metabolism of uric acid. The selected targets and targeting efficacy were validated using a rat model of hyperuricemia and renal injury induced by a high-fat and high-fructose diet.
Results: A total of 32 chemical components with effective targets, which regulated the PI3K-AKT pathway and endocrine resistance, were collected. Molecular docking results showed that iridoids and flavonoids are bound to proteins related to inflammation and uric acid metabolism. In addition, it was verified via animal experiments that an E. ulmoides leaf extract ameliorated hyperuricemia, renal injury, and inflammation, which are closely related to the targets Interleukin- 6 (IL-6), Tumor necrosis factor-α (TNF-α), Toll-Like Receptor 4 (TLR4), and Glucose transporter 9 (GLUT9). 
Conclusion: E. ulmoides leaf flavonoids and iridoids ameliorate hyperuricemia and uric-acid–induced inflammation through a multi-component, multi-target, and multi-pathway mechanism, which provides a theoretical basis for the development of therapeutics from E. ulmoides leaf components.


1. Caliceti C, Calabria D, Roda A, Cicero AFG. Fructose Intake, serum uric acid, and cardiometabolic disorders: A critical review. Nutrients 2017; 9: 395-409.
2. Nakagawa T, Tuttle KR, Short RA, Johnson RJ. Hypothesis: Fructose-induced hyperuricemia as a causal mechanism for the epidemic of the metabolic syndrome. Nat Clin Pract Nephrol 2005; 1:80-86.
3. Jia G, Habibi J, Bostick BP, Ma L, DeMarco VG, Aroor AR, et al. Uric acid promotes left ventricular diastolic dysfunction in mice fed a Western diet. Hypertension 2015; 65:531-539.
4. Stack AG, Hanley A, Casserly LF, Cronin CJ, Abdalla AA, Kiernan TJ, et al. Independent and conjoint associations of gout and hyperuricaemia with total and cardiovascular mortality. Qjm 2013; 106:647-658.
5. Braga TT, Foresto-Neto O, Camara NOS. The role of uric acid in inflammasome-mediated kidney injury. Curr Opin Nephrol Hypertens 2020; 29:423-431.
6. Zhang S, Wang Y, Cheng J, Huangfu N, Zhao R, Xu Z, et al. Hyperuricemia and cardiovascular disease. Curr Pharm Des 2019; 25:700-709.
7. Liu E, Han L, Wang J, He W, Shang H, Gao X, et al. Eucommia ulmoides bark protects against renal injury in cadmium-challenged rats. J Med Food 2012; 15:307-314.
8. Lee G, Lee H, Choi M, Choi A, Shin T, Chae H. Eucommia ulmoides leaf (EUL) extract enhances NO production in ox-LDL-treated human endothelial cells. Biomed Pharmacother 2018; 97:1164-1172.
9. Zhang Y, Zhang H, Wang F, Yang D, Ding K, Fan J. The ethanol extract of Eucommia ulmoides Oliv. leaves inhibits disaccharidase and glucose transport in Caco-2 cells. J Ethnopharmacol 2015; 163:99-105.
10. Hao S, Xiao Y, Lin Y, Mo Z, Chen Y, Peng X, et al. Chlorogenic acid-enriched extract from Eucommia ulmoides leaves inhibits hepatic lipid accumulation through regulation of cholesterol metabolism in HepG2 cells. Pharm Biol 2016; 54:251-259.
11. Lee G, Lee H, Park S, Shin T, Chae H. Eucommia ulmoides leaf extract ameliorates steatosis induced by high-fat diet in rats by increasing lysosomal function. Nutrients 2019; 11:426-440.
12. Wang C, Tang L, He J, Li J, Wang Y. Ethnobotany, phytochemistry and pharmacological properties of Eucommia ulmoides: A review. Am J Chin Med 2019; 47:259-300.
13. Fang C, Chen L, He M, Luo Y, Zhou M, Zhang N, et al. Molecular mechanistic insight into the anti-hyperuricemic effect of Eucommia ulmoides in mice and rats. Pharm Biol 2019; 57:112-119.
14. Suganthy N, Devi K, Nabavi S, Braidy N, Nabavi S. Bioactive effects of quercetin in the central nervous system: Focusing on the mechanisms of actions. Biomed  Pharmacother 2016; 84:892-908.
15. Hosoo S, Koyama M, Watanabe A, Ishida R, Hirata T, Yamaguchi Y, et al. Preventive effect of Eucommia leaf extract on aortic media hypertrophy in Wistar-Kyoto rats fed a high-fat diet. Hypertens Res 2017; 40:546-551.
16. Garofalo C, De Stefano T, Vita C, Vinci G, Balia F, Nettuno F, et al. [Hyperuricaemia and Chronic Kidney Disease]. G Ital Nefrol 2018; 35:2018.
17. Landolfo M, Borghi C. Hyperuricaemia and vascular risk: the debate continues. Curr Opin Cardiol 2019; 34:399-405.
18. Borghi C, Agabiti-Rosei E, Johnson RJ, Kielstein JT, Lurbe E, Mancia G, et al. Hyperuricaemia and gout in cardiovascular, metabolic and kidney disease. Eur J Intern Med 2020; 80:1-11.
19. Shekelle P, Newberry S, FitzGerald J, Motala A, O’Hanlon C, Tariq A, et al. Management of gout: A systematic review in support of an american college of physicians clinical practice guideline. Ann Intern Med 2017; 166:37-51.
20. Masuda T, Shingai Y, Takahashi C, Inai M, Miura Y, Honda S, et al. Identification of a potent xanthine oxidase inhibitor from oxidation of caffeic acid. Free Radic Biol Med 2014; 69:300-307.
21. Ling X, Bochu W. A review of phytotherapy of gout: Perspective of new pharmacological treatments. Pharmazie 2014; 69:243-256.
22. Liu L, Zhao T, Shan L, Cao L, Zhu X, Xue Y. Estradiol regulates intestinal ABCG2 to promote urate excretion via the PI3K/Akt pathway. Nutr Metab (Lond) 2021; 18:63-73.
23. So A. Developments in the scientific and clinical understanding of gout. Arthritis Res Ther 2008; 10:221-226.
24. Jin M, Yang F, Yang I, Yin Y, Luo JJ, Wang H, et al. Uric acid, hyperuricemia and vascular diseases. Front Biosci (Landmark Ed) 2012; 17:656-669.
25. Joosten LAB, Crişan TO, Bjornstad P, Johnson RJ. Asymptomatic hyperuricaemia: A silent activator of the innate immune system. Nat Rev Rheumatol 2020; 16:75-86.
26. Tan J, Wan L, Chen X, Li X, Hao X, Li X, et al. Conjugated linoleic acid ameliorates high fructose-induced hyperuricemia and renal inflammation in rats via NLRP3 inflammasome and TLR4 signaling pathway. Mol Nutr Food Res 2019; 63:e1801402.
27. Yang Y, Zhang DM, Liu JH, Hu LS, Xue QC, Ding XQ, et al. Wuling san protects kidney dysfunction by inhibiting renal TLR4/MyD88 signaling and NLRP3 inflammasome activation in high fructose-induced hyperuricemic mice. J Ethnopharmacol 2015; 169:49-59.
28. Scuiller A, Pascart T, Bernard A, Oehler E. [Gout]. Rev Med Interne 2020; 41:396-403.
29. Wang M, Zhao J, Zhang N, Chen J. Astilbin improves potassium oxonate-induced hyperuricemia and kidney injury through regulating oxidative stress and inflammation response in mice. Biomed Pharmacother 2016; 83:975-988.
30. Zhou Y, Zhang X, Li C, Yuan X, Han L, Li Z, et al. Research on the pharmacodynamics and mechanism of fraxini cortex on hyperuricemia based on the regulation of URAT1 and GLUT9. Biomed Pharmacother 2018; 106:434-442.