Preventive effect of SA13353 [1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea], a novel transient receptor potential vanilloid 1 agonist, on ischemia/reperfusion-induced renal injury in rats.

Abstract

Tumor necrosis factor (TNF)-alpha plays a crucial role in the pathogenesis of ischemia/reperfusion-induced renal injury. We demonstrated recently that the preischemic treatment with resiniferatoxin, a transient receptor potential vanilloid 1 (TRPV1) agonist, attenuates renal TNF-alpha mRNA expression and improves ischemia/reperfusion-induced renal injury in rats. In addition, we found that SA13353 [1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea], a novel orally active TRPV1 agonist, inhibits TNF-alpha production through the activation of capsaicin-sensitive afferent neurons and reduces the severity of symptoms in established rat collagen-induced arthritis. In the present study, we investigated effects of treatment with SA13353 on ischemia/reperfusion-induced renal injury in rats. Ischemic acute kidney injury (AKI) was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function in vehicle-treated AKI rats markedly decreased at 24 h after reperfusion. Treatment with SA13353 (3, 10, and 30 mg/kg p.o.) 30 min before ischemia dose-dependently attenuated the ischemia/reperfusion-induced renal dysfunction. Histopathological examination of the kidney of AKI rats revealed severe renal damage, which were significantly suppressed by the SA13353 treatment. In renal tissues exposed to ischemia/reperfusion, neutrophil infiltration, superoxide production, TNF-alpha mRNA expression, and cytokine-induced neutrophil chemoattractant-1 mRNA expression were augmented, but these alterations were attenuated by the treatment with SA13353. On the other hand, ischemia/reperfusion-enhanced renal interleukin-10 mRNA expression and its plasma concentration were further augmented by SA13353 treatment. These results demonstrate that the orally active TRPV1 agonist SA13353 prevents the ischemia/reperfusion-induced AKI. This renoprotective effects seem to be closely related to the inhibition of inflammatory response via TRPV1 activation.

• Authors: Kyoko Ueda, Fumio Tsuji, Tomoko Hirata, Kenji Ueda, Masaaki Murai, Hiroyuki Aono, Masanori Takaoka, Yasuo Matsumura
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 329 Issue 1 Pg. 202-9 (Apr 2009) ISSN: 1521-0103 [Electronic] United States
• PMID: 19147859 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• 1-(2-(1-adamantyl)ethyl)-1-pentyl-3-(3-(4-pyridyl)propyl)urea
• Pyridines
• Reactive Oxygen Species
• TRPV Cation Channels
• TRPV1 receptor
• Tumor Necrosis Factor-alpha
• Interleukin-10
• RNA
• Urea

Topics

• Acute Disease
• Animals
• Interleukin-10 (physiology)
• Kidney Diseases (drug therapy, pathology)
• Kidney Function Tests
• Male
• Neutrophil Infiltration (drug effects)
• Pyridines (pharmacokinetics, therapeutic use)
• RNA (biosynthesis, genetics)
• Rats
• Rats, Sprague-Dawley
• Reactive Oxygen Species
• Reperfusion Injury (drug therapy, pathology)
• Reverse Transcriptase Polymerase Chain Reaction
• TRPV Cation Channels (agonists)
• Tumor Necrosis Factor-alpha (physiology)
• Urea (analogs & derivatives, pharmacokinetics, therapeutic use)