1. 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.
- Author
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Yang SM, Chan YL, Hua KF, Chang JM, Chen HL, Tsai YJ, Hsu YJ, Chao LK, Feng-Ling Y, Tsai YL, Wu SH, Wang YF, Tsai CL, Chen A, and Ka SM
- Subjects
- Active Transport, Cell Nucleus drug effects, Animals, Antioxidants metabolism, Cnidium metabolism, Cyclooxygenase 2 biosynthesis, Dinoprostone biosynthesis, Disease Models, Animal, Female, Glomerulosclerosis, Focal Segmental prevention & control, Glutathione Peroxidase metabolism, Heme Oxygenase-1 biosynthesis, Inflammation drug therapy, Macrophage Activation drug effects, Macrophages immunology, Membrane Proteins biosynthesis, Mice, Mice, Inbred BALB C, NF-kappa B antagonists & inhibitors, Oxidative Stress drug effects, Plant Preparations pharmacology, Podocytes drug effects, Podocytes pathology, Proteinuria drug therapy, Proteinuria prevention & control, Reactive Oxygen Species metabolism, Apoptosis drug effects, Calcium Channel Blockers pharmacology, Coumarins pharmacology, Glomerulosclerosis, Focal Segmental drug therapy, NF-E2-Related Factor 2 metabolism
- 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., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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