Metallothionein protects against the nephrotoxicity produced by chronic CdMT exposure.
Metallothionein protects against the nephrotoxicity produced by chronic CdMT exposure.
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DOI：
10.1093/toxsci/50.2.221
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发表时间：
1999-08
期刊：
影响因子：
--
通讯作者：
Y. Liu;J. Liu;S. Habeebu;C. Klaassen
中科院分区：
文献类型：
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作者：
Y. Liu;J. Liu;S. Habeebu;C. Klaassen
金属硫蛋白 (MT) 是一种低分子量、富含半胱氨酸的金属结合蛋白。 MT 的诱导被认为是降低镉毒性的重要适应性机制。 MT 已被证明可以防止 CdCl2 引起的致死和肝毒性；然而，MT 不能预防 CdMT 引起的急性肾毒性。本研究旨在阐明金属硫蛋白在慢性 CdMT 诱导的肾损伤中的作用。因此，野生型和 MT-I/II 敲除（MT-null）小鼠每天皮下注射 CdMT（25 和 100 微克 Cd/kg）或盐水，每周 6 次，持续 6 周，并评估肾损伤。向野生型小鼠多次注射 CdMT 导致肾脏 Cd 浓度高达 120 微克/克肾脏，同时肾脏 MT 增加 100 倍（450 微克/克肾脏）。相比之下，多次注射 CdMT 的 MT 缺失小鼠的肾脏 Cd 浓度达到比野生型小鼠低得多的水平（<10 microg/g 肾脏）。尽管肾脏中积累的镉较少，但 MT 缺失小鼠比野生型小鼠更容易受到 CdMT 诱导的肾毒性，如蛋白质和 N-乙酰-β-D-氨基葡萄糖苷酶的尿排泄增加以及血液尿素氮水平升高所示。在较高的每日 CdMT 剂量（100 微克 Cd/kg）下，MT 缺失小鼠的肾脏增大。慢性 CdMT 给药最终会损害整个肾脏，包括肾小球肿胀、间质炎症、水肿、肾小管细胞变性和萎缩。与单次注射 CdMT 会产生近端肾小管坏死相比，长期注射 CdMT 会导致野生型和 MT 缺失小鼠的肾小管细胞凋亡。这些数据表明，慢性 CdMT 施用产生与慢性 CdCl2 施用后观察到的相似的肾损伤，并且细胞内 MT 可以防止慢性 CdMT 施用产生的肾毒性。
Metallothionein (MT) is a low-molecular-weight, cysteine-rich, metal-binding protein. Induction of MT has been proposed to be an important adaptive mechanism in decreasing Cd toxicity. MT has been shown to protect against CdCl2-induced lethality and hepatotoxicity; however, MT does not protect against acute CdMT-induced nephrotoxicity. This study was aimed at clarifying the role of metallothionein in chronic CdMT-induced renal injury. Wild type and MT-I/II knockout (MT-null) mice were therefore given sc injections of CdMT (25 and 100 microg Cd/kg) or saline daily, 6 times/week for 6 weeks, and renal injury was evaluated. Multiple injections of CdMT to wild-type mice resulted in renal Cd concentrations up to 120 microg/g kidney, along with a 100-fold increase in renal MT (450 microg/g kidney). In contrast, renal Cd concentration in MT-null mice administered multiple injections of CdMT reached a much lower level than in wild-type mice (<10 microg/g kidney). Although less Cd accumulated in their kidneys, MT-null mice were more susceptible than wild-type mice to CdMT-induced nephrotoxicity, as indicated by increased urinary excretion of protein and N-acetyl-beta-D-glucosaminidase, as well as by elevated blood urea nitrogen levels. At the higher daily dose of CdMT (100 microg Cd/kg), kidneys of MT-null mice were enlarged. Chronic CdMT administration eventually damaged the entire kidney, which included glomerular swelling, interstitial inflammation, edema, tubular cell degeneration, and atrophy. In contrast to a single injection of CdMT that produces proximal tubular necrosis, chronic injection of CdMT results in tubular cell apoptosis in both wild-type and MT-null mice. These data indicate that chronic CdMT administration produces similar renal injury to that observed after chronic CdCl2 administration, and that intracellular MT protects against nephrotoxicity produced by chronic CdMT administration.