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Free Radic Biol Med. 2014 Aug;73:260-9. doi: 10.1016/j.freeradbiomed.2014.05.009. Epub 2014 May 22.

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 information

  • 1Department of Pathology and National Defense Medical Center, Taipei 114, Taiwan, Republic of China.
  • 2Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan, Republic of China.
  • 3Institute for Drug Evaluation Platform, Development Center for Biotechnology, Taipei, Taiwan, Republic of China.
  • 4Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital; National Defense Medical Center, Taipei 114, Taiwan, Republic of China.
  • 5Department of Cosmeceutics, China Medical University, Taichung, Taiwan, Republic of China.
  • 6Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan, Republic of China.
  • 7Graduate Institute of Life Sciences; and National Defense Medical Center, Taipei 114, Taiwan, Republic of China.
  • 8Graduate Institute of Electrical Engineering and Computer Science, National Penghu University of Science and Technology, Penghu, Taiwan, Republic of China.
  • 9Graduate Institute of Aerospace and Undersea Medicine, School of Medicine; National Defense Medical Center, Taipei 114, Taiwan, Republic of China. Electronic address: shukmanka@gmail.com.

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.

KEYWORDS:

Accelerated focal segmental glomerulosclerosis; Glomerular epithelial hyperplasia lesions; Glomerular hyalinosis/sclerosis; Nrf2 pathway; Osthole; Periglomerular inflammation; Reactive oxygen species

PMID:
24858719
[PubMed - indexed for MEDLINE]
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