rhADAMTS13 reduces oxidative stress by cleaving VWF in ischemia/reperfusion induced acute kidney injury
rhADAMTS13 reduces oxidative stress by cleaving VWF in ischemia/reperfusion induced acute kidney injury
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rhADAMTS13 通过裂解 VWF 来减少缺血/再灌注引起的急性肾损伤中的氧化应激
DOI：
10.1111/apha.13778
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
En Yin Lai
中科院分区：
文献类型：
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作者：
Suhan Zhou;Jie Guo;Xinxin Liao;Qin Zhou;Xingyu Qiu;Shan Jiang;Nan Xu;Xiaohua Wang;Liang Zhao;Weipeng Hu;Lanyu Xie;Peng Xie;Yu Cui;Yi Yang;Andreas Patzak;Pontus B Persson;Jianhua Mao;En Yin Lai
急性肾损伤（阿基）是一个主要的健康负担，缺乏有效的治疗。具有血小板反应蛋白1型基序成员13（ADAMTS 13）的去整合素和金属蛋白酶的抗炎作用可能为阿基提供新的治疗选择。沿着炎症，氧化应激是阿基发展的关键，但ADAMTS 13对阿基中氧化应激的影响仍有待充分阐明。MethodsWe评估重组人ADAMTS 13（rhADAMTS 13）在小鼠缺血/再灌注（IR）模型中对氧化应激的作用。结果缺血再灌注后24 h，rhADAMTS 13可使血尿素氮（BUN）和血肌酐（Scr）分别降低33%和73%。在IR后48小时，rhADAMTS 13也使BUN（40.03 ± 20.34 mmol/L vs 72.35 ± 18.74 mmol/L，P<0.01）、Scr（75.67 ± 51.19 μmol/L vs 176.17 ± 55.38 μmol/L，P<0.01）和蛋白尿减少41%。此外，rhADAMTS 13给药降低了丙二醛（MDA），增加了抗氧化应激酶的活性，并减弱了活性氧的产生。rhADAMTS 13还上调核因子-红细胞-2-相关因子2/血红素加氧酶-1，增强抗氧化酶活性并减轻内皮功能障碍。最后，用rhADAMTS 13治疗减轻IR小鼠中存在的严重功能和形态学损伤。细胞外信号调节激酶（ERK）磷酸化受到rhADAMTS 13的限制，并且在缺血肾脏中部分恢复了PPARγ表达。结论rhADAMTS 13通过切割血管性血友病因子（vonWillebrand factor，VWF）发挥抗氧化作用，减轻肾缺血再灌注损伤。
AimsAcute kidney injury (AKI), a major health burden, lacks effective therapy. Anti‐inflammatory actions of a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13 (ADAMTS13) may provide a new treatment option for AKI. Along with inflammation, oxidative stress is critical for AKI development, yet the impact of ADAMTS13 on oxidative stress in AKI remains to be fully elucidated.MethodsWe assess recombinant human ADAMTS13 (rhADAMTS13) actions on oxidative stress in a murine ischaemia/reperfusion (IR) model. Antioxidant stress‐enzyme activities, renal morphology, kidney function markers and vascular function of isolated afferent arterioles are quantified.ResultsrhADAMTS13 provided after IR, reduces blood urea nitrogen (BUN) by 33% and serum creatinine (Scr) by 73% in 24 hours post‐IR. rhADAMTS13 reduces BUN (40.03 ± 20.34 mmol/L vs 72.35 ± 18.74 mmol/L,P< .01), Scr (75.67 ± 51.19 μmol/L vs 176.17 ± 55.38 μmol/L,P< .01) and proteinuria by 41% in 48 hours post‐IR as well. Moreover, rhADAMTS13 administration decreases malondialdehyde (MDA) and increases the activity of antioxidant stress enzymes, and attenuates reactive oxygen species production. rhADAMTS13 also upregulates nuclear factor‐erythroid‐2‐related factor 2/haem oxygenase‐1, enhances antioxidant enzymes activity and alleviates endothelial dysfunction. Finally, treatment with rhADAMTS13 mitigates severe functional and morphological injury present in IR mice. Extracellular signal‐regulated kinase (ERK) phosphorylation is limited by rhADAMTS13 and PPARγ expression is partly restored in ischaemic kidneys. Co‐administration of von Willebrand factor (VWF) impairs rhADAMTS13’s antioxidant capacity and its protective role in IR.ConclusionrhADAMTS13 alleviates renal IR injury through antioxidant effects by cleaving VWF.