Increased R-spondin 3 contributes to aerobic exercise-induced protection against renal vascular endothelial hyperpermeability and acute kidney injury
Increased R-spondin 3 contributes to aerobic exercise-induced protection against renal vascular endothelial hyperpermeability and acute kidney injury
复制标题
DOI：
10.1111/apha.14036
复制
发表时间：
2023-08-21
影响因子：
6.3
通讯作者：
Zhu，Xiao-Yan
中科院分区：
文献类型：
--
作者：
Xu，Qing-Feng;Zhang，Hui;Zhu，Xiao-Yan
目的运动训练对脓毒症相关的多器官功能障碍具有保护作用。本研究旨在探讨有氧运动是否通过调节R‐spondin 3（RSPO 3）表达来预防脓毒症相关的急性肾损伤（阿基）。方法为了研究有氧运动对脂多糖（LPS）诱导的阿基的影响，在6周的跑台训练后腹腔注射LPS（20 mg/kg）。为了研究RSPO 3在LPS诱导的阿基中的作用，向野生型（WT）或诱导型内皮细胞特异性RSPO 3敲除（RSPO 3EC −/−）小鼠腹腔内注射12 mg/kg LPS。在LPS treatment.ResultsAerobic exercise-trained mice 30 min前腹腔注射RSPO 3对LPS诱导的体重减轻和体温降低有更强的抵抗力，并且比暴露于LPS的久坐小鼠有更高的存活率。运动训练恢复了LPS诱导的血清和肾脏RSPO 3水平降低。运动或RSPO 3减弱，而诱导型内皮细胞特异性RSPO 3敲除加重LPS诱导的肾糖萼丢失、内皮通透性过高、炎症和阿基。生物信息学分析结果显示，暴露于脓毒症或内毒素血症的小鼠肾组织中基质金属蛋白酶（MMPs）的表达显著增加，这在LPS暴露小鼠和LPS处理的人微血管内皮细胞（HMVECs）的肾组织中得到验证。RSPO 3和MMPs抑制剂都恢复了LPS诱导的紧密连接蛋白、粘附连接蛋白和糖萼成分的下调，从而改善了LPS诱导的内皮渗漏。运动或RSPO 3逆转了LPS诱导的肾组织中MMPs的上调.ConclusionIncreased renal expression of RSPO 3有助于有氧运动诱导的保护作用，通过抑制MMPs介导的糖萼、紧密连接和粘附连接的破坏，对抗LPS诱导的肾内皮细胞通透性增高和阿基。
AimExercise training exerts protective effects against sepsis‐associated multiple organ dysfunction. This study aimed to investigate whether aerobic exercise protected against sepsis‐associated acute kidney injury (AKI) via modulating R‐spondin 3 (RSPO3) expression.MethodsTo investigate the effects of aerobic exercise on lipopolysaccharide (LPS)‐induced AKI, LPS (20 mg/kg) was intraperitoneally injected after six weeks of treadmill training. To investigate the role of RSPO3 in LPS‐induced AKI, wild‐type (WT) or inducible endothelial cell‐specific RSPO3 knockout (RSPO3EC−/−) mice were intraperitoneally injected with 12 mg/kg LPS. RSPO3 was intraperitoneally injected 30 min before LPS treatment.ResultsAerobic exercise‐trained mice were more resistant to LPS‐induced body weight loss and hypothermia and had a significant higher survival rate than sedentary mice exposed to LPS. Exercise training restored the LPS‐induced decreases in serum and renal RSPO3 levels. Exercise or RSPO3 attenuated, whereas inducible endothelial cell‐specific RSPO3 knockout exacerbated LPS‐induced renal glycocalyx loss, endothelial hyperpermeability, inflammation, and AKI. Bioinformatics analysis results revealed significant increases in the expression of matrix metalloproteinases (MMPs) in kidney tissues of mice exposed to sepsis or endotoxaemia, which was validated in renal tissue from LPS‐exposed mice and LPS‐treated human microvascular endothelial cells (HMVECs). Both RSPO3 and MMPs inhibitor restored LPS‐induced downregulation of tight junction protein, adherens junction protein, and glycocalyx components, thus ameliorating LPS‐induced endothelial leakage. Exercise or RSPO3 reversed LPS‐induced upregulation of MMPs in renal tissues.ConclusionIncreased renal expression of RSPO3 contributes to aerobic exercise‐induced protection against LPS‐induced renal endothelial hyperpermeability and AKI by suppressing MMPs‐mediated disruption of glycocalyx and tight and adherens junctions.