title: 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.affiliation: Laboratory of Pathological and Molecular Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka 569-1094, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Ueda
authors.forename: Fumio
authors.initials: F
authors.lastname: Tsuji
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hirata
authors.forename: Kenji
authors.initials: K
authors.lastname: Ueda
authors.forename: Masaaki
authors.initials: M
authors.lastname: Murai
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aono
authors.forename: Masanori
authors.initials: M
authors.lastname: Takaoka
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Matsumura
mesh_terms: D000208:Acute Disease; D000818:Animals; D016753:Interleukin-10 / Q000502:physiology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D020556:Neutrophil Infiltration / Q000187:drug effects; D011725:Pyridines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050916:TRPV Cation Channels / Q000819:agonists*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D014508:Urea / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: C530925:1-(2-(1-adamantyl)ethyl)-1-pentyl-3-(3-(4-pyridyl)propyl)urea; D011725:Pyridines; D017382:Reactive Oxygen Species; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D012313:RNA; D014508:Urea