Effects of protease activated receptor (PAR)2 blocking peptide on endothelin-1 levels in kidney tissues in endotoxemic rat mode.

Abstract

AIMS:

Septic shock, the severe form of sepsis, is associated with development of progressive damage in multiple organs. Kidney can be injured and its functions altered by activation of coagulation, vasoactive-peptide and inflammatory processes in sepsis. Endothelin (ET)-1, a potent vasoconstrictor, is implicated in the pathogenesis of sepsis and its complications. Protease-activated receptors (PARs) are shown to play an important role in the interplay between inflammation and coagulation. We examined the time-dependent alterations of ET-1 and inflammatory cytokine, such as tumor necrosis factor (TNF)-α in kidney tissue in lipopolysaccharide (LPS)-induced septic rat model and the effects of PAR2 blocking peptide on the LPS-induced elevations of renal ET-1 and TNF-α levels.

MAIN METHODS:

Male Wistar rats at 8 weeks of age were administered with either saline solution or LPS at different time points (1, 3, 6 and 10h). Additionally, we treated LPS-administered rats with PAR2 blocking peptide for 3h to assess whether blockade of PAR2 has a regulatory role on the ET-1 level in septic kidney.

KEY FINDINGS:

An increase in ET-1 peptide level was observed in kidney tissue after LPS administration time-dependently. Levels of renal TNF-α peaked (around 12-fold) at 1h of sepsis. Interestingly, PAR2 blocking peptide normalized the LPS-induced elevations of renal ET-1 and TNF-α levels.

SIGNIFICANCE:

The present study reveals a distinct chronological expression of ET-1 and TNF-α in LPS-administered renal tissues and that blockade of PAR2 may play a crucial role in treating renal injury, via normalization of inflammation, coagulation and vaso-active peptide.

• Authors: Subrina Jesmin, Nobutake Shimojo, Naoto Yamaguchi, Chishimba Nathan Mowa, Masami Oki, Sohel Zaedi, Sayeeda Nusrat Sultana, Arifur Rahman, Majedul Islam, Atsushi Sawamura, Satoshi Gando, Satoru Kawano, Takashi Miyauchi, Taro Mizutani
• Journal: Life sciences (Life Sci) Vol. 102 Issue 2 Pg. 127-33 (May 02 2014) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 24641950 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Endothelin-1
• Lipopolysaccharides
• Peptide Fragments
• Receptor, PAR-2
• Tumor Necrosis Factor-alpha

Topics

• Animals
• Disease Models, Animal
• Endothelin-1 (antagonists & inhibitors, biosynthesis, metabolism)
• Endotoxemia (chemically induced, drug therapy, metabolism)
• Kidney Diseases (chemically induced, drug therapy, metabolism)
• Lipopolysaccharides (administration & dosage)
• Male
• Peptide Fragments (pharmacology, therapeutic use)
• Rats
• Rats, Wistar
• Receptor, PAR-2 (antagonists & inhibitors, metabolism)
• Treatment Outcome
• Tumor Necrosis Factor-alpha (metabolism)