血红素加氧酶1与肾脏缺血再灌注损伤：免疫抑制药物的影响

Heme oxygenase 1 and renal ischemia and reperfusion injury: the impact of immunosuppressive drug.

作者信息

Gonçalves Giselle Martins, Cenedeze Marcos Antônio, Feitoza Carla Quarim, de Paula Carolina Batista, Macusso Georgia Daniela, Pinheiro Helady Sanders, Teixeira Vicente de Paula Antunes, dos Reis Marlene Antônia, Pacheco-Silva Alvaro, Câmara Niels Olsen Saraiva

机构信息

Laboratório de Imunologia Clínica e Experimental, Division of Nephrology, Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, Brazil.

出版信息

Int Immunopharmacol. 2006 Dec 20;6(13-14):1966-72.

PMID:17219692

Abstract

UNLABELLED

Ischemia and reperfusion injury (IRI) is the main etiology of acute renal failure in native and transplanted kidneys. In the transplantation field, immunosuppressive drugs may play an additional role in acute graft dysfunction. Acute cyclosporine nephrotoxicity (ATN) can result from vasoconstriction of the afferent arterioles, which may exacerbate deceased renal transplantation. HO-1 is a protective gene with anti-inflammatory and anti-apoptotic actions. We investigated whether HO-1 played a role in cyclosporine-induced renal dysfunction in an established model of IRI.

METHODS

Cyclosporine (100 mg/kg) was administered to mice before being subjected to 45 min of ischemia. Blood and kidney samples were collected at 24, 48 and 120 h after surgery. Acute tubular necrosis and tubular regeneration were quantified. HO-1 gene transcripts were amplified by real-time PCR.

RESULTS

Animals subjected to IRI presented with impaired renal function that peaked at 24 h (2.05 +/- 0.23 mg/dL), decreasing thereafter. Treatment with cyclosporine caused even more renal dysfunction at 48 h, sustained up to 120 h after reperfusion (1.53 +/- 0.6 mg/dL), when compared to the controls (0.63 +/- 0.09 mg/dL, p < 0,05). Cyclosporine delayed tubular regeneration that was normally higher in controls at day 5 (67.0% vs. 37.6%, p < 0.05). HO-1 was markedly up-regulated after IRI, and its expression was decreased by cyclosporine (2.06 folds). However, prior induction of HO-1 by cobalt protoporphyrin improved renal dysfunction.

CONCLUSIONS

These results demonstrated that cyclosporine used in ischemic injured organs might also negatively affect post-transplantation recovery.

摘要

未标记

缺血再灌注损伤（IRI）是自体肾和移植肾急性肾衰竭的主要病因。在移植领域，免疫抑制药物可能在急性移植物功能障碍中起额外作用。急性环孢素肾毒性（ATN）可由入球小动脉血管收缩导致，这可能会加重尸体肾移植的情况。HO-1是一种具有抗炎和抗凋亡作用的保护基因。我们研究了在已建立的IRI模型中HO-1是否在环孢素诱导的肾功能障碍中发挥作用。

方法

在对小鼠进行45分钟缺血之前给予环孢素（100mg/kg）。在手术后24、48和120小时采集血液和肾脏样本。对急性肾小管坏死和肾小管再生进行定量分析。通过实时PCR扩增HO-1基因转录本。

结果

遭受IRI的动物出现肾功能受损，在24小时达到峰值（2.05±0.23mg/dL），此后逐渐下降。与对照组（0.63±0.09mg/dL，p<0.05）相比，环孢素治疗在48小时导致更严重的肾功能障碍，在再灌注后120小时仍持续存在（1.53±0.6mg/dL）。环孢素延迟了肾小管再生，在第5天对照组的肾小管再生通常更高（67.0%对37.6%，p<0.05）。IRI后HO-1明显上调，其表达被环孢素降低（2.06倍）。然而，用原卟啉钴预先诱导HO-1可改善肾功能障碍。