Zhang Yue, Sun Ying, Ding Guixia, Huang Songming, Zhang Aihua, Jia Zhanjun
1] Department of Nephrology, Nanjing Children's Hospital, Affiliated with Nanjing Medical University, Nanjing 210008, China [2] Institute of Pediatrics, Nanjing Medical University, Nanjing, China [3] Nanjing Key Laboratory of Pediatrics, Nanjing Children Hospital, Affiliated with Nanjing Medical University, Nanjing 210008, China.
Sci Rep. 2015 Jul 24;5:12480. doi: 10.1038/srep12480.
Ureteral obstruction with subsequent hydronephrosis is a common clinical complication. Downregulation of renal sodium transporters in obstructed kidneys could contribute to impaired urinary concentrating capability and salt waste following the release of a ureteral obstruction. The current study was undertaken to investigate the role of mitochondrial complex-1 inhibition in modulating sodium transporters in obstructive kidney disease. Following unilateral ureteral obstruction (UUO) for 7 days, a global reduction of sodium transporters, including NHE3, α-Na-K-ATPase, NCC, NKCC2, p-NKCC2, ENaCα, and ENaCγ, was observed, as determined via qRT-PCR and/or Western blotting. Interestingly, inhibition of mitochondrial complex-1 by rotenone markedly reversed the downregulation of NKCC2, p-NKCC2, and ENaCα. In contrast, other sodium transporters were not affected by rotenone. To study the potential mechanisms involved in mediating the effects of rotenone on sodium transporters, we examined a number of known sodium modulators, including PGE2, ET1, Ang II, natriuretic peptides (ANP, BNP, and CNP), and nitric oxide synthases (iNOS, nNOS, and eNOS). Importantly, among these modulators, only BNP and iNOS were significantly reduced by rotenone treatment. Collectively, these findings demonstrated a substantial role of mitochondrial dysfunction in mediating the downregulation of NKCC2 and ENaCα in obstructive kidney disease, possibly via iNOS-derived nitric oxide and BNP.
输尿管梗阻继发肾积水是一种常见的临床并发症。梗阻性肾脏中肾钠转运体的下调可能导致输尿管梗阻解除后尿浓缩能力受损和盐分流失。本研究旨在探讨线粒体复合物-1抑制在调节梗阻性肾病中钠转运体的作用。单侧输尿管梗阻(UUO)7天后,通过qRT-PCR和/或蛋白质印迹法测定,观察到包括NHE3、α-Na-K-ATP酶、NCC、NKCC2、p-NKCC2、ENaCα和ENaCγ在内的钠转运体整体减少。有趣的是,鱼藤酮抑制线粒体复合物-1可显著逆转NKCC2、p-NKCC2和ENaCα的下调。相比之下,其他钠转运体不受鱼藤酮影响。为了研究介导鱼藤酮对钠转运体作用的潜在机制,我们检测了一些已知的钠调节剂,包括前列腺素E2、内皮素-1、血管紧张素II、利钠肽(心房钠尿肽、脑钠肽和C型钠尿肽)以及一氧化氮合酶(诱导型一氧化氮合酶、神经元型一氧化氮合酶和内皮型一氧化氮合酶)。重要的是,在这些调节剂中,只有脑钠肽和诱导型一氧化氮合酶在鱼藤酮处理后显著降低。总的来说,这些发现表明线粒体功能障碍在介导梗阻性肾病中NKCC2和ENaCα的下调中起重要作用,可能是通过诱导型一氧化氮合酶衍生的一氧化氮和脑钠肽实现的。