{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T18:49:37Z","timestamp":1782931777033,"version":"3.54.5"},"reference-count":44,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,10,29]],"date-time":"2020-10-29T00:00:00Z","timestamp":1603929600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2017R1A5A2015805"],"award-info":[{"award-number":["2017R1A5A2015805"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2019R1I1A3A01062432"],"award-info":[{"award-number":["2019R1I1A3A01062432"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Gynura divaricata (L.) DC (Compositae) (GD) could be found in various parts of Asia. It has been used as a traditional medicine to treat diabetes, high blood pressure, and other diseases, but its effects have not yet been scientifically confirmed. Therefore, we aimed at determining whether GD could affect renal function regulation, blood pressure, and the renin-angiotensin-aldosterone system (RAAS). Cardio-renal syndrome (CRS) is a disease caused by the interaction between the kidney and the cardiovascular system, where the acute or chronic dysfunction in one organ might induce acute or chronic dysfunction of the other. This study investigated whether GD could improve cardio-renal mutual in CRS type 4 model animals, two-kidney one-clip (2K1C) renal hypertensive rats. The experiments were performed on the following six experimental groups: control rats (CONT); 2K1C rats (negative control); OMT (Olmetec, 10 mg\/kg\/day)-treated 2K1C rats (positive control); and 2K1C rats treated with GD extracts in three different doses (50, 100, and 200 mg\/kg\/day) for three weeks by oral intake. Each group consisted of 10 rats. We measured the systolic blood pressure weekly using the tail-cuff method. Urine was also individually collected from the metabolic cage to investigate the effect of GD on the kidney function, monitoring urine volume, electrolyte, osmotic pressure, and creatinine levels from the collected urine. We observed that kidney weight and urine volume, which would both display typically increased values in non-treated 2K1C animals, significantly decreased following the GD treatment (###p &lt; 0.001 vs. 2K1C). Osmolality and electrolytes were measured in the urine to determine how renal excretory function, which is reduced in 2K1C rats, could be affected. We found that the GD treatment improved renal excretory function. Moreover, using periodic acid-Schiff staining, we confirmed that the GD treatment significantly reduced fibrosis, which is typically increased in 2K1C rats. Thus, we confirmed that the GD treatment improved kidney function in 2K1C rats. Meanwhile, we conducted blood pressure and vascular relaxation studies to determine if the GD treatment could improve cardiovascular function in 2K1C rats. The heart weight percentages of the left atrium and ventricle were significantly lower in GD-treated 2K1C rats than in non-treated 2K1C rats. These results showed that GD treatment reduced cardiac hypertrophy in 2K1C rats. Furthermore, the acetylcholine-, sodium nitroprusside-, and atrial natriuretic peptide-mediated reduction of vasodilation in 2K1C rat aortic rings was also ameliorated by GD treatment (GD 200 mg\/kg\/day; p &lt; 0.01, p &lt; 0.05, and p &lt; 0.05 vs. 2K1C for vasodilation percentage in case of each compound). The mRNA expression in the 2K1C rat heart tissue showed that the GD treatment reduced brain-type natriuretic peptide and troponin T levels (p &lt; 0.001 and p &lt; 0.001 vs. 2K1C). In conclusion, this study showed that GD improved the cardiovascular and renal dysfunction observed in an innovative hypertension model, highlighting the potential of GD as a therapeutic agent for hypertension. These findings indicate that GD shows beneficial effects against high blood pressure by modulating the RAAS in the cardio-renal syndrome. Thus, it should be considered an effective traditional medicine in hypertension treatment.<\/jats:p>","DOI":"10.3390\/nu12113321","type":"journal-article","created":{"date-parts":[[2020,10,29]],"date-time":"2020-10-29T09:44:53Z","timestamp":1603964693000},"page":"3321","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Antihypertensive Effects of Gynura divaricata (L.) DC in Rats with Renovascular Hypertension"],"prefix":"10.3390","volume":"12","author":[{"given":"Mi Hyeon","family":"Hong","sequence":"first","affiliation":[{"name":"College of Oriental Medicine and Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Korea"},{"name":"Hanbang Cardio-renal Research Center &amp; Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian Jun","family":"Jin","sequence":"additional","affiliation":[{"name":"College of Oriental Medicine and Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung Joo","family":"Yoon","sequence":"additional","affiliation":[{"name":"College of Oriental Medicine and Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Korea"},{"name":"Hanbang Cardio-renal Research Center &amp; Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9347-8606","authenticated-orcid":false,"given":"Yun Jung","family":"Lee","sequence":"additional","affiliation":[{"name":"College of Oriental Medicine and Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Korea"},{"name":"Hanbang Cardio-renal Research Center &amp; Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun Cheol","family":"Oh","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Wonkwang University, Iksan 54538, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ho Sub","family":"Lee","sequence":"additional","affiliation":[{"name":"College of Oriental Medicine and Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Korea"},{"name":"Hanbang Cardio-renal Research Center &amp; Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye Yoom","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Oriental Medicine and Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Korea"},{"name":"Hanbang Cardio-renal Research Center &amp; Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dae Gill","family":"Kang","sequence":"additional","affiliation":[{"name":"College of Oriental Medicine and Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Korea"},{"name":"Hanbang Cardio-renal Research Center &amp; Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e952","DOI":"10.1097\/MD.0000000000000952","article-title":"Prevalence and incidence of hypertension in the general adult population","volume":"94","author":"Lacruz","year":"2015","journal-title":"Medicine"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/j.jash.2016.08.006","article-title":"Worldwide prevalence of hypertension exceeds 1.3 billion","volume":"10","author":"Bloch","year":"2016","journal-title":"J. Am. Soc. Hypertens."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1097\/01.hco.0000167719.37700.1d","article-title":"Endothelial dysfunction: Its role in hypertensive coronary disease","volume":"20","author":"Bolad","year":"2005","journal-title":"Curr. Opin. Cardiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1152\/ajpregu.00305.2018","article-title":"Relation between resting sympathetic outflow and vasoconstrictor responses to sympathetic nerve bursts: Sex differences in healthy young adults","volume":"316","author":"Robinson","year":"2019","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.7150\/ijbs.7502","article-title":"The Vascular Endothelium and Human Diseases","volume":"9","author":"Peramaiyan","year":"2013","journal-title":"Int. J. Biol. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4","DOI":"10.2174\/157016112798829760","article-title":"The role of nitric oxide on endothelial function","volume":"10","author":"Tousoulis","year":"2012","journal-title":"Curr. Vasc. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3182","DOI":"10.1073\/pnas.1321871111","article-title":"Hydrogen sulfide cytoprotective signaling is endothelial nitric oxide synthase-nitric oxide dependent","volume":"111","author":"King","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"222","DOI":"10.5830\/CVJA-2011-068","article-title":"Endothelial dysfunction: The early predictor of atherosclerosis","volume":"23","author":"Mudau","year":"2012","journal-title":"Cardiovasc. J. Afr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.jdiacomp.2018.10.003","article-title":"Endothelial cell-specific overexpression of endothelial nitric oxide synthase in Ins2Akita mice exacerbates diabetic nephropathy","volume":"33","author":"Natarajan","year":"2018","journal-title":"J. Diabetes Complicat."},{"key":"ref_10","first-page":"657","article-title":"Correlation analysis of levels of inflammatory cytokines and nitric oxide in peripheral blood with urine proteins and renal function in patients with gestational hypertension","volume":"13","author":"Zhang","year":"2019","journal-title":"Exp. Ther. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/hr.2011.39","article-title":"Oxidative stress and endothelial dysfunction in hypertension","volume":"34","author":"Schulz","year":"2011","journal-title":"Hypertens. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1016\/j.jacc.2013.04.091","article-title":"Right ventricular dysfunction and remodeling in chronic obstructive pulmonary disease without pulmonary hypertension","volume":"62","author":"Hilde","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_13","first-page":"340","article-title":"Hemolysis during cardiac surgery is associated with increased intravascular nitric oxide consumption and perioperative kidney and intestinal tissue damage","volume":"5","author":"Wit","year":"2014","journal-title":"Front. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6255","DOI":"10.1113\/JP272708","article-title":"Carotid sinus denervation ameliorates renovascular hypertension in adult Wistar rats","volume":"594","author":"Pijacka","year":"2016","journal-title":"J. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.carpath.2015.11.003","article-title":"Resveratrol improves vasoprotective effects of captopril on aortic remodeling and fibrosis triggered by renovascular hypertension","volume":"25","author":"Natalin","year":"2016","journal-title":"Cardiovasc. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1002\/jcb.26258","article-title":"Vaccarin administration ameliorates hypertension and cardiovascular remodeling in renovascular hypertensive rats","volume":"119","author":"Zhu","year":"2018","journal-title":"J. Cell. Biochem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1161\/HYPERTENSIONAHA.118.12425","article-title":"Dietary nitrate reduces blood pressure in rats with angiotensin II\u2013induced hypertension via mechanisms that involve reduction of sympathetic hyperactivity","volume":"73","author":"Cruz","year":"2019","journal-title":"Hypertension"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Yu, T.T., Guo, K., Chen, H.C., Lan, C.Z., Wang, J., Huang, L.L., and Wang, X.H. (2013). Effects of traditional Chinese medicine Xin-Ji-Er-Kang formula on 2K1C hypertensive rats: Role of oxidative stress and endothelial dysfunction. BMC Complement. Altern. Med., 13.","DOI":"10.1186\/1472-6882-13-173"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1186\/s13098-015-0095-3","article-title":"DPP-4 inhibitor sitagliptin prevents inflammation and oxidative stress of heart and kidney in two kidney and one clip (2K1C) rats","volume":"7","author":"Alam","year":"2015","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Campagnaro, B.P., Gava, A.L., Meyrelles, S.S., and Vasquez, E.C. (2012). Cardiac-autonomic imbalance and baroreflex dysfunction in the renovascular angiotensin-dependent hypertensive mouse. Int. J. Hypertens., 968123.","DOI":"10.1155\/2012\/968123"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"8686297","DOI":"10.1155\/2018\/8686297","article-title":"The aqueous extract of Gynura divaricata (L.) DC improves glucose and lipid metabolism and ameliorates type 2 diabetes mellitus","volume":"2018","author":"Li","year":"2018","journal-title":"Evid. Based Complement. Alternat. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.jep.2011.04.059","article-title":"In vitro studies of Gynura divaricata (L.) DC extracts as inhibitors of key enzymes relevant for type 2 diabetes and hypertension","volume":"136","author":"Wu","year":"2011","journal-title":"J. Ethnopharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"113","DOI":"10.21010\/ajtcam.v14i3.12","article-title":"Bioactive components of Gynura divaricate and its potential use in health, food and medicine: A mini-review","volume":"14","author":"Xu","year":"2017","journal-title":"Afr. J. Tradit. Complement. Altern. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"114","DOI":"10.2141\/jpsa.0180112","article-title":"Effect of dietary inclusion of Gynura divaricate (L.) on growth performance, hematology, and carcass fat deposition in broilers","volume":"57","author":"Jamjang","year":"2020","journal-title":"J. Poult. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1159\/000100391","article-title":"Inhibition of angiotensin-converting enzyme activity by partially purified fraction of Gynura procumbens in spontaneously hypertensive rats","volume":"16","author":"Hoe","year":"2007","journal-title":"Med. Princ. Pract."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1161\/HYPERTENSIONAHA.120.15026","article-title":"International Society of Hypertension Global Hypertension Practice Guidelines","volume":"75","author":"Unger","year":"2020","journal-title":"J. Hypertens."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1007\/s11906-019-0949-4","article-title":"New approaches in hypertension management: A review of current and developing technologies and their potential impact on hypertension care","volume":"21","author":"Kitt","year":"2019","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1161\/HYPERTENSIONAHA.119.14240","article-title":"High blood pressure and cardiovascular disease","volume":"75","author":"Fuchs","year":"2020","journal-title":"Hypertension"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1681\/ASN.V1171287","article-title":"Renal enlargement precedes renal hyperfiltration in early experimental diabetes in rats","volume":"11","author":"Bak","year":"2000","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1161\/CIRCULATIONAHA.112.093245","article-title":"The assessment of endothelial function-from research into clinical practice","volume":"126","author":"Flammer","year":"2012","journal-title":"Circulation"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1152\/ajprenal.00459.2011","article-title":"Endothelial dysfunction promotes the transition from compensatory renal hypertrophy to kidney injury after unilateral nephrectomy in mice","volume":"302","author":"Nagasu","year":"2012","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.ceca.2017.06.003","article-title":"Acetylcholine induces intracellular Ca2+ oscillations and nitric oxide release in mouse brain endothelial cells","volume":"66","author":"Zuccolo","year":"2017","journal-title":"Cell Calcium"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5682","DOI":"10.1111\/bph.12870","article-title":"Endothelin-1 contributes to endothelial dysfunction and enhanced vasoconstriction through augmented superoxide production in penile arteries from insulin-resistant obese rats: Role of ETA and ETB receptors","volume":"171","author":"Benedito","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/j.lfs.2012.02.006","article-title":"ET-1 from endothelial cells is required for complete angiotensin II-induced cardiac fibrosis and hypertrophy","volume":"91","author":"Adiarto","year":"2012","journal-title":"Life Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1161\/CIRCRESAHA.116.303587","article-title":"Hypertension: Renin-angiotensin-aldosterone system alterations","volume":"116","author":"Roks","year":"2015","journal-title":"Circ. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"16","DOI":"10.4314\/ajtcam.v11i5.3","article-title":"Beneficial therapeutic effect of Chinese herbal Xinji\u2019Erkang formula on hypertension-induced renal injury in the 2-kidney-1-clip hypertensive rats","volume":"11","author":"Huang","year":"2014","journal-title":"Arf. J. Tradit. Complement. Altern. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.hfc.2013.12.003","article-title":"Cardiorenal syndrome","volume":"10","author":"Ronco","year":"2014","journal-title":"Heart Fail. Clin."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.semnephrol.2011.11.006","article-title":"Cardio-renal syndrome type 4: Epidemiology, pathophysiology and treatment","volume":"32","author":"House","year":"2012","journal-title":"Semin. Nephrol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1016\/j.jep.2014.07.006","article-title":"Effects of Xin-Ji-Er-Kang formula on 2K1C-induced hypertension and cardiovascular remodeling in rats","volume":"155","author":"Guo","year":"2014","journal-title":"J. Ethnopharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.hfc.2018.03.005","article-title":"Biomarkers in pulmonary hypertension","volume":"14","author":"Marra","year":"2018","journal-title":"Heart Fail. Clin."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.jjcc.2010.01.008","article-title":"N-terminal pro-BNP is a novel biomarker for integrated cardio-renal burden and early risk stratification in patients admitted for cardiac emergency","volume":"55","author":"Yamashita","year":"2010","journal-title":"J. Cardiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1161\/HYPERTENSIONAHA.114.04206","article-title":"High sensitivity troponin T and cardiovascular events in systolic blood pressure categories: Atherosclerosis risk in communities study","volume":"65","author":"Pokharel","year":"2015","journal-title":"Hypertension"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"292","DOI":"10.3724\/SP.J.1263.2012.02291","article-title":"Cardiorenal biomarkers in acute heart failure","volume":"9","author":"Choudhary","year":"2012","journal-title":"J. Geriatr. Cardiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.semnephrol.2011.11.011","article-title":"Role of biomarkers in the diagnosis and management of cardio-renal syndromes","volume":"32","author":"Cruz","year":"2011","journal-title":"Semin. Nephrol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/11\/3321\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:26:17Z","timestamp":1760178377000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/11\/3321"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,29]]},"references-count":44,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["nu12113321"],"URL":"https:\/\/doi.org\/10.3390\/nu12113321","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,29]]}}}