Inhibition of Mitochondrial Complex-1 Prevents the Downregulation of NKCC2 and ENaCα in Obstructive Kidney Disease.
Inhibition of Mitochondrial Complex-1 Prevents the Downregulation of NKCC2 and ENaCα in Obstructive Kidney Disease.
复制标题
抑制线粒体复合物-1 可防止梗阻性肾病中 NKCC2 和 ENaC α 的下调
DOI：
10.1038/srep12480
复制
发表时间：
2015-07-24
影响因子：
4.6
通讯作者：
Jia Z
中科院分区：
文献类型：
--
作者：
Zhang Y;Sun Y;Ding G;Huang S;Zhang A;Jia Z
输尿管梗阻并发肾积水是常见的临床并发症。梗阻肾脏中肾钠转运蛋白的下调可能导致输尿管梗阻解除后尿浓缩能力受损和盐的浪费。目前的研究是为了研究线粒体复合物-1抑制在调节阻塞性肾病钠转运蛋白中的作用。单侧输尿管梗阻（UUO） 7天后，通过qRT-PCR和/或Western blotting检测，观察到钠转运体（包括NHE3、α- na - k - atp酶、NCC、NKCC2、p-NKCC2、ENaCα和ENaCγ）的整体减少。有趣的是，鱼烯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，其他钠转运蛋白不受鱼藤酮的影响。为了研究鱼藤酮介导钠转运蛋白作用的潜在机制，我们研究了许多已知的钠调节剂，包括PGE2、ET1、Ang II、利钠肽（ANP、BNP和CNP）和一氧化氮合酶（iNOS、nNOS和eNOS）。重要的是，在这些调节剂中，只有BNP和iNOS被鱼藤酮显著降低。总的来说，这些发现证明了线粒体功能障碍在阻塞性肾病中介导NKCC2和ENaCα下调的重要作用，可能是通过inos衍生的一氧化氮和BNP。
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.