Wu Hao, Zhou Shanshan, Kong Lili, Chen Jing, Feng Wenke, Cai Jun, Miao Lining, Tan Yi
Department of Nephrology, The Second Hospital of Jilin University, Changchun, China; Kosair Children's Hospital Research Institute, Department of Pediatrics, The University of Louisville, Louisville, KY, USA.
Kosair Children's Hospital Research Institute, Department of Pediatrics, The University of Louisville, Louisville, KY, USA; Cardiovascular Center, The First Hospital of Jilin University, Changchun, China.
Toxicol Lett. 2015 Jan 22;232(2):340-8. doi: 10.1016/j.toxlet.2014.11.015. Epub 2014 Nov 15.
As a main clinical feature of obstructive sleep apnea (OSA), intermittent hypoxia (IH) induces oxidative stress, leading to damage to a variety of organs, including kidney. Metallothionein (MT) is a potent antioxidant that protects kidney against oxidative damage. Our previous studies demonstrated that MT prevented IH-induced cardiomyopathy in mice. However, the role of MT in protecting against IH-induced renal injury is unknown. Therefore, MT knockout (MT KO) mice and wild type (WT) control mice (129S) were culled for exposure to intermittent air as control or IH for a time course of 3 days, 1 week, 3 weeks and 8 weeks. MT KO mice developed higher urinary albumin to creatinine ratio (UACR) after exposure to IH for 8 weeks. Compared with either MT KO control or WT IH mice, MT deletion significantly aggravated IH-induced renal oxidative damage and inflammation at all four time points, along with significant acceleration of renal fibrosis after exposure to IH for 3 weeks and 8 weeks. Antioxidants including MT, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase 1 (HO1) and NAD (P) H dehydrogenase [quinone] 1 (NQO1) were increased in response to short-term IH (3 days, 1 week and 3 weeks) but decreased after long-term IH (8 weeks) in WT mice. Interestingly, Nrf2, HO1 and NQO1 were significantly attenuated under IH conditions in the absence of MT, which were in parallel with the inactivation of protein kinase B (Akt) and extracellular signal-regulated kinase (ERK). These findings demonstrated that MT played a key role in preventing IH-induced renal injury possibly via preserving Nrf2 signaling pathway.
作为阻塞性睡眠呼吸暂停（OSA）的主要临床特征，间歇性缺氧（IH）会引发氧化应激，导致包括肾脏在内的多种器官受损。金属硫蛋白（MT）是一种强大的抗氧化剂，可保护肾脏免受氧化损伤。我们之前的研究表明，MT可预防小鼠因间歇性缺氧引起的心肌病。然而，MT在预防间歇性缺氧诱导的肾损伤中的作用尚不清楚。因此，将MT基因敲除（MT KO）小鼠和野生型（WT）对照小鼠（129S品系）处死，使其暴露于间歇性空气（作为对照）或间歇性缺氧环境中，持续3天、1周、3周和8周。暴露于间歇性缺氧8周后，MT KO小鼠的尿白蛋白与肌酐比值（UACR）升高。与MT KO对照小鼠或WT间歇性缺氧小鼠相比，在所有四个时间点，MT缺失均显著加重了间歇性缺氧诱导的肾氧化损伤和炎症，并且在暴露于间歇性缺氧3周和8周后，肾纤维化明显加速。在野生型小鼠中，包括MT、核因子（红系衍生2）样2（Nrf2）、血红素加氧酶1（HO1）和NAD（P）H脱氢酶[醌]1（NQO1）在内的抗氧化剂在短期间歇性缺氧（3天、1周和3周）后增加，但在长期间歇性缺氧（8周）后减少。有趣的是，在缺乏MT的情况下，间歇性缺氧条件下Nrf2、HO1和NQO1显著减弱，这与蛋白激酶B（Akt）和细胞外信号调节激酶（ERK）的失活平行。这些发现表明，MT可能通过维持Nrf2信号通路在预防间歇性缺氧诱导的肾损伤中起关键作用。
