title: Osthole improves an accelerated focal segmental glomerulosclerosis model in the early stage by activating the Nrf2 antioxidant pathway and subsequently inhibiting NF-κB-mediated COX-2 expression and apoptosis.
abstract: Inflammatory reactions and oxidative stress are implicated in the pathogenesis of focal segmental glomerulosclerosis (FSGS), a common chronic kidney disease with relatively poor prognosis and unsatisfactory treatment regimens. Previously, we showed that osthole, a coumarin compound isolated from the seeds of Cnidium monnieri, can inhibit reactive oxygen species generation, NF-κB activation, and cyclooxygenase-2 expression in lipopolysaccharide-activated macrophages. In this study, we further evaluated its renoprotective effect in a mouse model of accelerated FSGS (acFSGS), featuring early development of proteinuria, followed by impaired renal function, glomerular epithelial cell hyperplasia lesions (a sensitive sign that precedes the development of glomerular sclerosis), periglomerular inflammation, and glomerular hyalinosis/sclerosis. The results show that osthole significantly prevented the development of the acFSGS model in the treated group of mice. The mechanisms involved in the renoprotective effects of osthole on the acFSGS model were mainly a result of an activated Nrf2-mediated antioxidant pathway in the early stage (proteinuria and ischemic collapse of the glomeruli) of acFSGS, followed by a decrease in: (1) NF-κB activation and COX-2 expression as well as PGE2 production, (2) podocyte injury, and (3) apoptosis. Our data support that targeting the Nrf2 antioxidant pathway may justify osthole being established as a candidate renoprotective compound for FSGS.
authors.affiliation: Department of Pathology and National Defense Medical Center, Taipei 114, Taiwan, Republic of China.
authors.forename: Shun-Min
authors.initials: SM
authors.lastname: Yang
authors.affiliation: Department of Pathology and National Defense Medical Center, Taipei 114, Taiwan, Republic of China.
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Chan
authors.affiliation: Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan, Republic of China.
authors.forename: Kuo-Feng
authors.initials: KF
authors.lastname: Hua
authors.affiliation: Institute for Drug Evaluation Platform, Development Center for Biotechnology, Taipei, Taiwan, Republic of China.
authors.forename: Jia-Ming
authors.initials: JM
authors.lastname: Chang
authors.affiliation: Institute for Drug Evaluation Platform, Development Center for Biotechnology, Taipei, Taiwan, Republic of China.
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Chen
authors.affiliation: Institute for Drug Evaluation Platform, Development Center for Biotechnology, Taipei, Taiwan, Republic of China.
authors.forename: Yung-Jen
authors.initials: YJ
authors.lastname: Tsai
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital; National Defense Medical Center, Taipei 114, Taiwan, Republic of China.
authors.forename: Yu-Juei
authors.initials: YJ
authors.lastname: Hsu
authors.affiliation: Department of Cosmeceutics, China Medical University, Taichung, Taiwan, Republic of China.
authors.forename: Louis Kuoping
authors.initials: LK
authors.lastname: Chao
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan, Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Feng-Ling
authors.affiliation: Graduate Institute of Life Sciences; and National Defense Medical Center, Taipei 114, Taiwan, Republic of China.
authors.forename: Yu-Ling
authors.initials: YL
authors.lastname: Tsai
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan, Republic of China.
authors.forename: Shih-Hsiung
authors.initials: SH
authors.lastname: Wu
authors.affiliation: Graduate Institute of Electrical Engineering and Computer Science, National Penghu University of Science and Technology, Penghu, Taiwan, Republic of China.
authors.forename: Yih-Fuh
authors.initials: YF
authors.lastname: Wang
authors.affiliation: Graduate Institute of Electrical Engineering and Computer Science, National Penghu University of Science and Technology, Penghu, Taiwan, Republic of China.
authors.forename: Change-Ling
authors.initials: CL
authors.lastname: Tsai
authors.affiliation: Department of Pathology and National Defense Medical Center, Taipei 114, Taiwan, Republic of China.
authors.forename: Ann
authors.initials: A
authors.lastname: Chen
authors.affiliation: Graduate Institute of Aerospace and Undersea Medicine, School of Medicine; National Defense Medical Center, Taipei 114, Taiwan, Republic of China. Electronic address: shukmanka@gmail.com.
authors.forename: Shuk-Man
authors.initials: SM
authors.lastname: Ka
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D031048:Cnidium / Q000378:metabolism; D003374:Coumarins / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D015232:Dinoprostone / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy* / Q000517:prevention & control; D005979:Glutathione Peroxidase / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D007249:Inflammation / Q000188:drug therapy; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000276:immunology; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D018384:Oxidative Stress / Q000187:drug effects; D028321:Plant Preparations / Q000494:pharmacology; D050199:Podocytes / Q000187:drug effects / Q000473:pathology; D011507:Proteinuria / Q000188:drug therapy / Q000517:prevention & control; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D002121:Calcium Channel Blockers; D003374:Coumarins; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; D028321:Plant Preparations; D017382:Reactive Oxygen Species; D005979:Glutathione Peroxidase; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone; C046627:osthol
keywords: Accelerated focal segmental glomerulosclerosis; Glomerular epithelial hyperplasia lesions; Glomerular hyalinosis/sclerosis; Nrf2 pathway; Osthole; Periglomerular inflammation; Reactive oxygen species