title: Genipin ameliorates hypertension-induced renal damage via the angiotensin II-TLR/MyD88/MAPK pathway.
abstract: Genipin is a major active component of Fructus Gardenia, which has been widely used in Traditional Chinese Medicine for the treatment of various cardiovascular diseases. The aim of this study was to investigate the potential effects of genipin on hypertension and the related nephropathy and elucidate the underlying mechanisms of action. We first examined the effects of genipin on blood pressure and renal functions in the Spontaneously Hypertensive (SHR) rats. In the subsequent experiments with human mesangial cells (HMCs), the effects of genipin on angiotensin II (Ang II)-induced HMC proliferation, reactive oxygen species (ROS) generation, and cytokine prodution were examined using the MTT method, 2',7'-dichlorohydrofluorescein (DCFH-DA) staining, and the corresponding enzyme-linked immunosorbent assay (ELISA) kits, respectively. The effects of genipin on Ang II-induced activation of the MAPK pathway and up-regulation of TLR2, TLR4, and MyD88 were detected by real-time PCR and Western blot and further validated in MyD88 siRNA-transfected HMCs. Genipin not only significantly lowered blood pressure in SHR rats after an 8-week treatment, but effectively improved renal functions, evidenced by decreased serum creatinine and blood urea nitrogen (BUN), as well as urinary microalbumin (m-ALB) and N-acetyl-beta-d-glucosaminidase (NAG) upon administration with genipin. Mechanistic studies conducted in Ang II-treated HMCs showed that genipin was able to counteract Ang II-induced cell proliferation, ROS generation, and pro-inflammatory responses. These effects may be mediated through the TLR/MyD88/MAPK signaling pathway. These findings provide new insights into the molecular mechanisms of genipin in the treatment of renal damage in hypertension, which merits a further investigation.
authors.affiliation: Department of Cardiology, Yantaishan Hospital, Yantai, Shandong, Province, 264001, China.
authors.forename: Dawei
authors.initials: D
authors.lastname: Yu
authors.affiliation: Department of Cardiology, Yantai Affiliated Hospital of Binzhou Medical College, Yantai, Shandong, Province, 264003, China.
authors.forename: Mengsong
authors.initials: M
authors.lastname: Shi
authors.affiliation: Second Department of Internal Medicine, Yantaishan Hospital, Yantai, Shandong, Province, 264001, China.
authors.forename: Jinwei
authors.initials: J
authors.lastname: Bao
authors.affiliation: Department of Cardiology, Yantaishan Hospital, Yantai, Shandong, Province, 264001, China.
authors.forename: Xinyan
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Cardiology, Yantaishan Hospital, Yantai, Shandong, Province, 264001, China.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Cardiology, Yantaishan Hospital, Yantai, Shandong, Province, 264001, China. Electronic address: dr.liuwenbo@gmail.com.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Liu
mesh_terms: D000804:Angiotensin II; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D039823:Iridoids / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D011918:Rats, Inbred SHR; D017382:Reactive Oxygen Species / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D000959:Antihypertensive Agents; D016207:Cytokines; D039823:Iridoids; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D017382:Reactive Oxygen Species; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D000804:Angiotensin II; C007834:genipin
keywords: Angiotensin II; Genipin; Human mesangial cells; Hypertension; Toll-like receptors