Role of mitochondria' oxidative stress in modulating the expressions of aquaporins in obstructive kidney disease
Role of mitochondria' oxidative stress in modulating the expressions of aquaporins in obstructive kidney disease
复制标题
线粒体氧化应激在调节阻塞性肾病中水通道蛋白表达中的作用。
DOI：
10.1152/ajprenal.00234.2017
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发表时间：
2018-04-01
影响因子：
4.2
通讯作者：
Jia, Zhanjun
中科院分区：
文献类型：
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作者：
Liu, Mi;Sun, Ying;Jia, Zhanjun
水通道蛋白（AQP）在梗阻性肾病中的下调已被充分证实，其机制尚不清楚。我们以前的研究表明，线粒体功能障碍在这一过程中起着至关重要的作用。然而，目前尚不清楚线粒体功能障碍如何影响水通道蛋白在梗阻性肾病。本研究探讨了动脉源性氧化应激在介导阻塞诱导的AQPs下调中的作用。单侧输尿管梗阻7天后，肾脏超氧化物歧化酶2（SOD 2;输尿管特异性SOD）减少了85%。同时，AQP 1、AQP 2、AQP 3. Western blotting和/或实时定量PCR检测显示，AQP 4表达显著下调。管理的SOD 2模拟锰（III）四（4-苯甲酸）卟啉氯化物（MnTBAP）显着衰减AQP 2下调与硫代巴比妥酸反应性物质升高的完全阻断一致，而减少AQP 1，AQP 3和AQP 4不受影响。环氧化酶（考克斯）-2/前列腺素（PG）E-2通路是梗阻性肾脏AQP降低的重要因素，因此，我们检测了肾脏中考克斯-1/2和微粒体前列腺素E合成酶1（mPGES-1）的水平以及尿液中PGE（2）的分泌。值得注意的是，MnTBAP部分抑制了考克斯-2、mPGES-1和PGE的升高（2）。MnTBAP处理后，V2受体明显减少，V2受体明显恢复。然而，纤维化反应和肾小管损伤不受MnTBAP在梗阻性肾脏。总之，这些发现提示线粒体氧化应激可能通过调节考克斯-2/mPGES-1/PGE（2）/V-2受体通路在介导梗阻性肾脏AQP 2下调中发挥重要作用。
Downregulation of aquaporins (AQPs) in obstructive kidney disease has been well demonstrated with elusive mechanisms. Our previous study indicated that mitochondrial dysfunction played a crucial role in this process. However, it is still uncertain how mitochondrial dysfunction affected the AQPs in obstructive kidney disease. This study investigated the role of mitochondria-derived oxidative stress in mediating obstruction-induced downregulation of AQPs. After unilateral ureteral obstruction for 7 days, renal superoxide dismutase 2 (SOD2; mitochondria-specific SOD) was reduced by 85%. Meanwhile, AQP1, AQP2, AQP3. and AQP4 were remarkably downregulated as determined by Western blotting and/or quantitative real-time PCR. Administration of the SOD2 mimic manganese (III) tetrakis(4-benzoic acid)porphyrin chloride (MnTBAP) significantly attenuated AQP2 downregulation in line with complete blockade of thiobarbituric acid-reactive substances elevation, whereas the reduction of AQP1, AQP3, and AQP4 was not affected. The cyclooxygenase (COX)-2/prostaglandin (PG) E-2 pathway has been well documented as a contributor of AQP reduction in obstructed kidney; thus, we detected the levels of COX-1/2 and microsomal prostaglandin E synthase 1 (mPGES-1) in kidney and PGE(2) secretion in urine. Significantly, MnTBAP partially suppressed the elevation of COX-2, mPGES-1, and PGE(2) . Moreover, a marked decrease of V-2 receptor was significantly restored after MnTBAP treatment. However, the fibrotic response and renal tubular damage were unaffected by MnTBAP in obstructed kidneys. Collectively, these findings suggested an important role of mitochondrial oxidative stress in mediating AQP2 downregulation in obstructed kidney, possibly via modulating the COX-2/mPGES-1/PGE(2)/V-2 receptor pathway.