A new recombinant MnSOD prevents the Cyclosporine A-induced renal impairment
A new recombinant MnSOD prevents the Cyclosporine A-induced renal impairment
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DOI：
10.1093/ndt/gft020
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发表时间：
2013-08-01
影响因子：
6.1
通讯作者：
Capasso, Giovambattista
中科院分区：
文献类型：
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作者：
Damiano, Sara;Trepiccione, Francesco;Capasso, Giovambattista
背景。环孢素A （Cyclosporine A, CsA）是预防移植排斥反应和自身免疫性疾病最常用的抗钢嘌呤类药物之一。它的使用受到肾毒性作用的阻碍，即肾小球滤过率（GFR）和高血压的损害。有证据表明活性氧（ROS）在肾毒性中起因果作用。本研究旨在研究一种新的重组线粒体含锰超氧化物歧化酶（rMnSOD）对csa诱导的ne光性的体内影响。大鼠单用CsA （25 mg/kg/天）或联合rMnSOD （10 μ g/kg/天）治疗7天。在治疗结束时，通过菊粉清除率（mL/min/100 g b.w.）估计GFR，并通过插入颈动脉的导管记录平均动脉压（MAP）。通过氧化二氢乙啶（DHE）测定腹主动脉细胞内超氧化物浓度。在肾脏组织中，ROS水平通过2070二氯荧光素双乙酸测定法测定。在组织化学水平上检查肾脏形态。csa处理的大鼠GFR严重下降（0.34 +/- 0.17，对照组0.94 +/- 0.10,P < 0.001）， rMnSOD联合给药（0.77 +/- 0.10）阻止了这种下降。注射csa的动物血压升高，rMnSOD对其无影响。CsA治疗后主动脉和肾组织中的ROS水平均显著升高，与rMnSOD联合给药后ROS水平恢复正常。这种效果在一定程度上与csa诱导的形态学损伤的恢复是一致的。rMnSOD可防止csa介导的GFR损伤和形态学改变。这种作用可能与活性氧的抑制有关。
Background. Cyclosporine A (CsA) is one of the most frequently used anticalcineurinic drugs for preventing graft rejection and autoimmune disease. Its use is hampered by nephrotoxic effects, namely an impairment of the glomerular filtration rate (GFR) and hypertension. Evidence suggests that reactive oxygen species (ROS) play a causal role in the nephrotoxicity. The present study aims to investigate in vivo the effects of a new recombinant mitochondrial manganese-containing superoxide dismutase (rMnSOD), a strong antioxidant, on the CsA-induced nephotoxicity.Methods. Rats were treated with CsA (25 mg/kg/day) alone or in combination with rMnSOD (10 mu g/kg/day) for 7 days. At the end of the treatment, GFR was estimated by inulin clearance (mL/min/100 g b.w.) and the mean arterial pressure (MAP) was recorded through a catheter inserted in the carotid artery. Superoxide concentration within the cells of the abdominal aorta was quantified from the oxidation of dihydroethidium (DHE). In kidney tissues, ROS levels were measured by the 2070 dichloroflurescin diacetate assay. Renal morphology was examined at the histochemistry level.Results. CsA-treated rats showed a severe decrease in GFR (0.34 +/- 0.17 versus 0.94 +/- 0.10 in control, P < 0.001) which was prevented by rMnSOD co-administration (0.77 +/- 0.10). CsA-injected animals presented with higher blood pressure which was unaffected by rMnSOD. ROS levels both in the aorta and in renal tissue were significantly increased by CsA treatment, and normalized by the co-administration with rMnSOD. This effect was, partly, paralleled by the recovery from CsA-induced morphological lesions.Conclusions. Administration of rMnSOD prevents CsA-mediated impairment of the GFR along with morphological alteration. This effect could be related to the inhibition of ROS.