Zhou Suhan, Guo Jie, Liao Xinxin, Zhou Qin, Qiu Xingyu, Jiang Shan, Xu Nan, Wang Xiaohua, Zhao Liang, Hu Weipeng, Xie Lanyu, Xie Peng, Cui Yu, Yang Yi, Patzak Andreas, Persson Pontus B, Mao Jianhua, Lai En Yin
Kidney Disease Center of the First Affiliated Hospital and Department of Physiology, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou, China.
Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Acta Physiol (Oxf). 2022 Mar;234(3):e13778. doi: 10.1111/apha.13778. Epub 2022 Jan 17.
Acute 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.
We 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.
rhADAMTS13 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.
rhADAMTS13 alleviates renal IR injury through antioxidant effects by cleaving VWF.
急性肾损伤（AKI）是一项重大的健康负担，目前缺乏有效的治疗方法。含血小板反应蛋白基序的解聚素和金属蛋白酶13（ADAMTS13）的抗炎作用可能为AKI提供一种新的治疗选择。除炎症外，氧化应激对AKI的发展也至关重要，但ADAMTS13对AKI氧化应激的影响仍有待充分阐明。
我们评估重组人ADAMTS13（rhADAMTS13）在小鼠缺血/再灌注（IR）模型中对氧化应激的作用。对抗氧化应激酶活性、肾脏形态、肾功能标志物以及分离的入球小动脉的血管功能进行定量分析。
IR后给予rhADAMTS13，可使IR后24小时血尿素氮（BUN）降低33%，血清肌酐（Scr）降低73%。rhADAMTS13还可使IR后48小时的BUN（40.03±20.34 mmol/L对72.35±18.74 mmol/L，P<.01）、Scr（75.67±51.19 μmol/L对176.17±55.38 μmol/L，P<.01）降低，并使蛋白尿减少41%。此外，给予rhADAMTS13可降低丙二醛（MDA）水平，增加抗氧化应激酶的活性，并减少活性氧的产生。rhADAMTS13还上调核因子红系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，rhADAMTS13治疗减轻了IR小鼠中存在的严重功能和形态损伤。细胞外信号调节激酶（ERK）磷酸化受到rhADAMTS13的限制，缺血肾脏中PPARγ表达部分恢复。联合给予血管性血友病因子（VWF）会损害rhADAMTS13的抗氧化能力及其在IR中的保护作用。
rhADAMTS13通过切割VWF发挥抗氧化作用，减轻肾脏IR损伤。
