title: Effects of the Nrf2 Protein Modulator Salvianolic Acid A Alone or Combined with Metformin on Diabetes-associated Macrovascular and Renal Injury.
abstract: Nuclear factor E2-related factor 2 (Nrf2) is considered a promising target against diabetic complications such as cardiovascular diseases and diabetic nephropathy. Herein, we investigated the effects of a potential Nrf2 modulator, salvianolic acid A (SAA), which is a natural polyphenol, on diabetes-associated macrovascular and renal injuries in streptozotocin-induced diabetic mice. Given that lowering glucose is the first objective of diabetic patients, we also examined the effects of SAA combined with metformin (MET) on both complications. Our results showed that SAA significantly increased the macrovascular relaxation response to acetylcholine and sodium nitroprusside in diabetic mice. Interestingly, treatment with SAA alone only provided minor protection against renal injury, as reflected by minor improvements in impaired renal function and structure, despite significantly reduced oxidative stress observed in the diabetic kidney. We demonstrated that decreased oxidative stress and NF-κB p65 expression were associated with SAA-induced expression of Nrf2-responsive antioxidant enzymes heme oxygenase-1 (HO-1), NAD(P)H dehydrogenase (quinone) 1 (NQO-1), and glutathione peroxidase-1 (GPx-1) in vivo or in vitro, which suggested that SAA was a potential Nrf2 modulator. More significantly, compared with treatment with either SAA or MET alone, we found that their combination provided further protection against the macrovascular and renal injury, which was at least partly due to therapeutic activation of both MET-mediated AMP-activated protein kinase and SAA-mediated Nrf2/antioxidant-response element pathways. These findings suggested that polyphenol Nrf2 modulators, especially combined with drugs activating AMP-activated protein kinase, including hypoglycemic drugs, are worthy of further investigation to combat diabetic complications.
authors.affiliation: From the Institute of Materia Medica and.
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.affiliation: From the Institute of Materia Medica and.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050 and.
authors.forename: Lin-Lin
authors.initials: LL
authors.lastname: Ma
authors.affiliation: From the Institute of Materia Medica and.
authors.forename: Bi-Yu
authors.initials: BY
authors.lastname: Hou
authors.affiliation: From the Institute of Materia Medica and the State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Beijing 100037, China.
authors.forename: Yang-Yang
authors.initials: YY
authors.lastname: He
authors.affiliation: From the Institute of Materia Medica and.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: From the Institute of Materia Medica and.
authors.forename: Zi-Ran
authors.initials: ZR
authors.lastname: Niu
authors.affiliation: From the Institute of Materia Medica and.
authors.forename: Jun-Ke
authors.initials: JK
authors.lastname: Song
authors.affiliation: From the Institute of Materia Medica and.
authors.forename: Xiao-Cong
authors.initials: XC
authors.lastname: Pang
authors.affiliation: From the Institute of Materia Medica and.
authors.forename: Xiu-Ying
authors.initials: XY
authors.lastname: Yang
authors.affiliation: From the Institute of Materia Medica and dugh@imm.ac.cn.
authors.forename: Guan-Hua
authors.initials: GH
authors.lastname: Du
mesh_terms: D000475:Alkenes / Q000494:pharmacology*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003925:Diabetic Angiopathies / Q000188:drug therapy* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D059808:Polyphenols / Q000494:pharmacology*; D000094765:Glutathione Peroxidase GPX1
chemical_list: D000475:Alkenes; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D059808:Polyphenols; C568740:salvianolic acid; D008687:Metformin; D005979:Glutathione Peroxidase; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse
keywords: Nuclear factor 2 (erythroid-derived 2-like factor) (NFE2L2) (Nrf2); diabetes; diabetic macrovascular injury; diabetic nephropathy; metformin; oxidative stress; salvianolic acid A