RESUMO
Excessive immune responses induced by ischemia-reperfusion injury (IRI) are known to lead to necrotic and apoptotic cell death, and calcineurin plays a major role in this process. Calcineurin dephosphorylates the nuclear factor of activated T-cells (NFAT), permitting its translocation into the nucleus. As a result, calcineurin promotes the release of pro-inflammatory cytokines, such as tumor necrosis factor-alpha. The overproduction of pro-inflammatory cytokines causes renal cell death. Calcineurin activity is regulated by calpain, a cysteine protease present in the nucleus. Calpain-mediated proteolysis increases the phosphatase activity of calcineurin, resulting in NFAT dephosphorylation. This process has been studied in cardiomyocytes but its role in renal IRI is unknown. Thus, we examined whether calpain regulates calcineurin in renal tubule nuclei. We established an in vivo renal IRI model in mice and identified the protective role of a calcineurin inhibitor, FK506, in this process. Calcineurin is expressed in the nucleus, where it is present in its calpain-cleaved form. FK506 reduced nuclear expression of calcineurin and prevented calcineurin-mediated NFAT activation. Our study shows clearly that FK506 reduces calpain-mediated calcineurin activity. Consequently, calcineurin could not maintain NFAT activation. FK506 reduced renal cell death by suppressing the transcription of pro-inflammatory cytokine genes. This study provides evidence that FK506 protects against inflammation in a renal IRI mouse model. We also provided a mechanism of calcineurin action in the nucleus. Therefore, FK506 could improve renal function by decreasing calcineurin activity in both the cytoplasm and the nucleus of renal tubule cells.
Assuntos
Animais , Camundongos , Calcineurina , Calpaína , Morte Celular , Cisteína Proteases , Citocinas , Citoplasma , Inflamação , Miócitos Cardíacos , Proteólise , Traumatismo por Reperfusão , Linfócitos T , Tacrolimo , Fator de Necrose Tumoral alfaRESUMO
Excessive immune responses induced by ischemia-reperfusion injury (IRI) are known to lead to necrotic and apoptotic cell death, and calcineurin plays a major role in this process. Calcineurin dephosphorylates the nuclear factor of activated T-cells (NFAT), permitting its translocation into the nucleus. As a result, calcineurin promotes the release of pro-inflammatory cytokines, such as tumor necrosis factor-alpha. The overproduction of pro-inflammatory cytokines causes renal cell death. Calcineurin activity is regulated by calpain, a cysteine protease present in the nucleus. Calpain-mediated proteolysis increases the phosphatase activity of calcineurin, resulting in NFAT dephosphorylation. This process has been studied in cardiomyocytes but its role in renal IRI is unknown. Thus, we examined whether calpain regulates calcineurin in renal tubule nuclei. We established an in vivo renal IRI model in mice and identified the protective role of a calcineurin inhibitor, FK506, in this process. Calcineurin is expressed in the nucleus, where it is present in its calpain-cleaved form. FK506 reduced nuclear expression of calcineurin and prevented calcineurin-mediated NFAT activation. Our study shows clearly that FK506 reduces calpain-mediated calcineurin activity. Consequently, calcineurin could not maintain NFAT activation. FK506 reduced renal cell death by suppressing the transcription of pro-inflammatory cytokine genes. This study provides evidence that FK506 protects against inflammation in a renal IRI mouse model. We also provided a mechanism of calcineurin action in the nucleus. Therefore, FK506 could improve renal function by decreasing calcineurin activity in both the cytoplasm and the nucleus of renal tubule cells.
Assuntos
Animais , Camundongos , Calcineurina , Calpaína , Morte Celular , Cisteína Proteases , Citocinas , Citoplasma , Inflamação , Miócitos Cardíacos , Proteólise , Traumatismo por Reperfusão , Linfócitos T , Tacrolimo , Fator de Necrose Tumoral alfaRESUMO
A case is described of the staged surgical repair of thoracic aortic aneurysm after revascularization of single functioning ischemic kidney of a 68 year old man. A hitological evaluation of renal function was obtained before renal revascularization, which encouraging us to perform the repair of thoracic aortic aneurysm with less risk of post-surgical acute renal failure. In case of single ischemic kidney, renal revascularization should be preceded to other major surgeries in order to prevent renal shut down.
RESUMO
Calcium has been implicated as primary pathogenetic mediator of cellular injury under conditions or oxygen and substrate deprivation in the kidney as well as other tissues. According to various studies, calcium channel blockers may prevent metabolic disturbances and promote functional and structural recovery after ischemia. Verapamil is known to have many actions which may account for its beneficial effect in renal ischemia. The purpose of the present study was to determine the effects of verapamil on mitochondrial respiration of ischemic kidney in rabbits. 1. In normal kidneys, cortical mitochondria showed higher S3 respiration and ACR than medulla But S4 respiration was similar between cortex and medulla. 2. After renal artery clamping in normothermia, there was a marked decrease in S3 respiration, no significant changes in S4 respiration, and a decrease in the ACR in cortex. But in medulla, there were significant decrease in both S3 and S4 respiration with slight decrease in the ACR. 3. In regional hypothermic group, there were a decrease in S3 respiration and a decrease in the ACR on cortex. But S3 respiration and the ACR were significantly higher than those of normothermic group. 4. In verapamil treated group, there was a decrease in S3 respiration and a decrease in the ACR on cortex. But reduction rate of S3 respiration and the ACR was significantly lower than those of normothermic group. 5. In medulla, reduction rate of the ACR was not significantly different between three experimental groups. Above results suggested that verapamil has partial but significant protective effect in renal ischemia and achieve its effect by preserving mitochondrial functions. And also it was suggested that regional hypothermia had a superior protective effect compared with verapamil.