Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University , Nanjing , China.
Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University , Guangzhou , China.
Am J Physiol Renal Physiol. 2018 Apr 1;314(4):F658-F666. doi: 10.1152/ajprenal.00234.2017. Epub 2017 Dec 20.
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 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 secretion in urine. Significantly, MnTBAP partially suppressed the elevation of COX-2, mPGES-1, and PGE. Moreover, a marked decrease of V 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/V receptor pathway.
在梗阻性肾病中，水通道蛋白（AQP）的下调已经得到了很好的证明，但其机制尚不清楚。我们之前的研究表明，线粒体功能障碍在这个过程中起着关键作用。然而，线粒体功能障碍如何影响梗阻性肾病中的 AQP 仍然不确定。本研究探讨了线粒体来源的氧化应激在介导梗阻诱导的 AQP 下调中的作用。在单侧输尿管梗阻 7 天后，肾脏超氧化物歧化酶 2（SOD2；线粒体特异性 SOD）减少了 85%。同时，通过 Western blot 和/或实时定量 PCR 确定 AQP1、AQP2、AQP3 和 AQP4 显著下调。SOD2 模拟物锰（III）四（4-苯甲酸）卟啉氯化物（MnTBAP）的给药显著减轻了 AQP2 的下调，与完全阻断丙二醛反应物质升高一致，而 AQP1、AQP3 和 AQP4 的减少不受影响。环氧化酶（COX）-2/前列腺素（PG）E 途径已被充分证明是梗阻性肾脏中 AQP 减少的一个贡献因素；因此，我们检测了肾脏中 COX-1/2 和微粒体前列腺素 E 合酶 1（mPGES-1）的水平以及尿液中的 PGE 分泌。值得注意的是，MnTBAP 部分抑制了 COX-2、mPGES-1 和 PGE 的升高。此外，MnTBAP 处理后 V 受体的显著减少得到了显著恢复。然而，MnTBAP 对梗阻肾脏中的纤维化反应和肾小管损伤没有影响。总之，这些发现表明，线粒体氧化应激在介导梗阻性肾病中 AQP2 下调中起重要作用，可能通过调节 COX-2/mPGES-1/PGE/V 受体途径。
