Abstract
Tumor necrosis factor (TNF)-α 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-α mRNA expression, and improves ischemia/reperfusion-induced renal injury in rats. In the present study, we investigated effects of treatment with SA13353, a novel orally active TRPV1 agonist, 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, TNF-α and cytokine-induced neutrophil chemoattractant-1 mRNA expressions 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.
Highlights
Ischemic cell injury in the kidney occurs during cardiovascular surgery, shock, and transplantation, which may lead to acute kidney injury (AKI)
Tumor necrosis factor (TNF)-α is released during renal ischemia/reperfusion and plays an important role in the ensuing neutrophil-mediated kidney injury [4]
We investigated the effects of treatment with the transient receptor potential vanilloid 1 (TRPV1) agonist, SA13353, on the ischemic AKI in rats and evaluated the possible involvement of TNF-α and IL-10, and cytokine-induced neutrophil chemoattractant (CINC)-1 in the SA13353-induced actions
Summary
Ischemic cell injury in the kidney occurs during cardiovascular surgery, shock, and transplantation, which may lead to acute kidney injury (AKI). In an international investigation of the epidemiology of AKI, the period prevalence of AKI requiring renal replacement therapy in intensive care unit was approximately 5% and the hospital mortality was more than 50% [1]. Renal ischemia, followed by reperfusion, is one of the most common causes of AKI and places a significant burden on the health care system. AKI is caused by ischemic and nephrotoxic insults acting alone or in combination. It is associated with increased morbidity, prolonged hospitalizations, and increased mortality [2]. TNF-α is released during renal ischemia/reperfusion and plays an important role in the ensuing neutrophil-mediated kidney injury [4]. TNF-α up-regulates neutrophil adhesion molecules, in particular intercellular adhesion molecule-1, after renal ischemia/reperfusion, and this molecule plays an important role in tissue neutrophil influx
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