title: A novel mechanism of action for salidroside to alleviate diabetic albuminuria: effects on albumin transcytosis across glomerular endothelial cells.
abstract: Salidroside (SAL) is a phenylethanoid glycoside isolated from the medicinal plant Rhodiola rosea. R. rosea has been reported to have beneficial effects on diabetic nephropathy (DN) and high-glucose (HG)-induced mesangial cell proliferation. Given the importance of caveolin-1 (Cav-1) in transcytosis of albumin across the endothelial barrier, the present study was designed to elucidate whether SAL could inhibit Cav-1 phosphorylation and reduce the albumin transcytosis across glomerular endothelial cells (GECs) to alleviate diabetic albuminuria as well as to explore its upstream signaling pathway. To assess the therapeutic potential of SAL and the mechanisms involved in DN albuminuria, we orally administered SAL to db/db mice, and the effect of SAL on the albuminuria was measured. The albumin transcytosis across GECs was explored in a newly established in vitro cellular model. The ratio of albumin to creatinine was significantly reduced upon SAL treatment in db/db mice. SAL decreased the albumin transcytosis across GECs in both normoglycemic and hyperglycemic conditions. SAL reversed the HG-induced downregulation of AMP-activated protein kinase and upregulation of Src kinase and blocked the upregulation Cav-1 phosphorylation. Meanwhile, SAL decreased mitochondrial superoxide anion production and moderately depolarized mitochondrial membrane potential. We conclude that SAL exerts its proteinuria-alleviating effects by downregulation of Cav-1 phosphorylation and inhibition of albumin transcytosis across GECs. These studies provide the first evidence of interference with albumin transcytosis across GECs as a novel approach to the treatment of diabetic albuminuria.
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology and Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, China; and Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology and Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, China; and.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology and Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, China; and.
authors.forename: Tao
authors.initials: T
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology and Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, China; and.
authors.forename: Shasha
authors.initials: S
authors.lastname: Xing
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology and Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, China; and.
authors.forename: Jianghong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology and Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, China; and.
authors.forename: Jiangyang
authors.initials: J
authors.lastname: Chi
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology and Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, China; and.
authors.forename: Fang
authors.initials: F
authors.lastname: Bian
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology and Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, China; and.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology and Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, China; and.
authors.forename: Gao
authors.initials: G
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology and Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, China; and.
authors.forename: Xiangli
authors.initials: X
authors.lastname: Bai
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology and Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, China; and.
authors.forename: Guangjie
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology and Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, China; and Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China Jinsi@mail.hust.edu.cn.
authors.forename: Si
authors.initials: S
authors.lastname: Jin
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D000418:Albumins / Q000187:drug effects* / Q000378:metabolism; D000419:Albuminuria / Q000378:metabolism*; D000818:Animals; D051242:Caveolin 1 / Q000187:drug effects* / Q000378:metabolism; D003404:Creatinine / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005960:Glucosides / Q000494:pharmacology*; D066298:In Vitro Techniques; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010636:Phenols / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D057900:Transcytosis / Q000187:drug effects*; D019061:src-Family Kinases / Q000187:drug effects / Q000378:metabolism
chemical_list: D000418:Albumins; D051242:Caveolin 1; D005960:Glucosides; D010636:Phenols; D003404:Creatinine; D019061:src-Family Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose; C009172:rhodioloside
keywords: albumin; diabetic nephropathy; glomerular endothelial cell; salidroside; transcytosis