Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 73, Issue -, Pages 260-269Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2014.05.009
Keywords
Accelerated focal segmental glomerulosclerosis; Osthole; Glomerular epithelial hyperplasia lesions; Periglomerular inflammation; Glomerular hyalinosis/sclerosis; Reactive oxygen species; Nrf2 pathway
Funding
- National Science Council [NSC102-2321-B-016-002]
- Medical Affairs Bureau [103-M012]
- Tri-Service General Hospital, Taiwan, Republic of China [TSGH-C103-079]
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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-kappa B 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-kappa B activation and COX-2 expression as well as PGE(2) 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. (C) 2014 Elsevier Inc. All rights reserved.
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