Extracellular Superoxide Dismutase Protects against Proteinuric Kidney Disease
Extracellular Superoxide Dismutase Protects against Proteinuric Kidney Disease
复制标题
DOI：
10.1681/asn.2014060613
复制
发表时间：
2015-10-01
影响因子：
13.6
通讯作者：
Liu, Youhua
中科院分区：
文献类型：
--
作者：
Tan, Roderick J.;Zhou, Dong;Liu, Youhua
细胞外超氧化物歧化酶（EC-SOD），也称为SOD 3，是一种在正常成人肾脏中高水平表达的抗氧化剂。由于氧化应激导致多种肾脏损伤，我们假设EC-SOD可能在CKD进展中起保护作用。为了研究这一假设，我们使用了一种以蛋白尿和肾功能不全为特征的ADR肾病小鼠模型。我们发现EC-SOD水平在整个疾病进展过程中降低，并与NADPH氧化酶和氧化应激标志物水平升高相关。EC-SOD裸小鼠对ADR损伤敏感，如白蛋白尿、血清肌酐、组织损伤和氧化应激的增加所证明的。EC-SOD的缺乏导致NADPH氧化酶水平的增加和β-连环蛋白信号传导的增加，这已被证明是各种肾损伤的病理性。暴露EC-SOD无效小鼠慢性血管紧张素II输注或每日白蛋白注射也引起蛋白尿增加。相反，EC-SOD裸小鼠受到非蛋白尿性CKD诱导的单侧输尿管梗阻表现出与野生型小鼠相比没有差异。最后，我们还发现在人类CKD活检样本中EC-SOD降低，与我们在小鼠中的发现相似。因此，我们得出结论，EC-SOD在以蛋白尿为特征的CKD中具有保护作用。
Extracellular superoxide dismutase (EC-SOD), also known as SOD3, is an antioxidant expressed at high levels in normal adult kidneys. Because oxidative stress contributes to a variety of kidney injuries, we hypothesized that EC-SOD may be protective in CKD progression. To study this hypothesis, we used a murine model of ADR nephropathy characterized by albuminuria and renal dysfunction. We found that levels of EC-SOD diminished throughout the course of disease progression and were associated with increased levels of NADPH oxidase and oxidative stress markers. EC-SOD null mice were sensitized to ADR injury, as evidenced by increases in albuminuria, serum creatinine, histologic damage, and oxidative stress. The absence of EC-SOD led to increased levels of NADPH oxidase and an increase in p-catenin signaling, which has been shown to be pathologic in a variety of kidney injuries. Exposure of EC-SOD null mice to either chronic angiotensin II infusion or to daily albumin injections also caused increased proteinuria. In contrast, EC-SOD null mice subjected to nonproteinuric CKD induced by unilateral ureteral obstruction exhibited no differences compared with wild-type mice. Finally, we also found a decrease in EC-SOD in human CKD biopsy samples, similar to our findings in mice. Therefore, we conclude that EC-SOD is protective in CKDs characterized by proteinuria.