通过 NKCC2 重吸收铊会导致大鼠出现严重的急性肾损伤和外髓特异性钙晶体铸型。

IF 4.8 2区 医学 Q1 TOXICOLOGY Archives of Toxicology Pub Date : 2024-10-03 DOI:10.1007/s00204-024-03868-2
Kana Unuma, Shuheng Wen, Sho Sugahara, Shutaro Nagano, Toshihiko Aki, Tadayuki Ogawa, Shino Takeda-Homma, Masakazu Oikawa, Akihiro Tojo
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引用次数: 0

摘要

铊(Tl)是毒性最强的重金属之一,与意外中毒和凶杀有关。它可导致急性和慢性全身性疾病,包括胃肠道疾病、心血管疾病和肾衰竭。然而,很少有研究探讨铊诱发急性肾损伤(AKI)的机制。本研究采用生化和组织病理学检测方法,研究了腹腔注射硫酸铊(30 毫克/千克)后,铊对大鼠肾脏组织学和功能的毒性影响。给药五天后,大鼠的肾功能严重受损。低真空扫描电子显微镜检查发现,服用铊的大鼠外侧髓质中钙(Ca)沉积过多,尤其是在亨氏环的髓质粗升支(mTAL)中。Tl 在 mTAL 中积累,并伴随着该节段的线粒体功能障碍。Tl 负荷的大鼠表现出肾脏转运体和负责 mTAL 中 Ca2+ 重吸收的通道表达减少。预先服用 Na-K-Cl 共转运体 2(NKCC2)抑制剂呋塞米可减轻 mTAL 中的 Tl 积累和线粒体异常。这些研究结果表明,Tl 肾毒性与 mTAL 通过 NKCC2 优先重吸收 Tl 有关,从而导致 mTAL 线粒体功能障碍和 Ca2+ 重吸收紊乱,最终导致以 mTAL 为主导的 Ca 晶体沉积和 AKI。这些关于碲肾毒性机制的发现可能有助于开发新的治疗方法来对抗碲中毒。此外,在外髓质观察到特征性的钙晶体沉积,也为碲中毒的诊断难题提供了新的见解。
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Thallium reabsorption via NKCC2 causes severe acute kidney injury with outer medulla-specific calcium crystal casts in rats

Thallium (Tl) is one of the most toxic heavy metals, associated with accidental poisoning and homicide. It causes acute and chronic systemic diseases, including gastrointestinal and cardiovascular diseases and kidney failure. However, few studies have investigated the mechanism by which Tl induces acute kidney injury (AKI). This study investigated the toxic effects of Tl on the histology and function of rat kidneys using biochemical and histopathological assays after intraperitoneal thallium sulfate administration (30 mg/kg). Five days post-administration, rats exhibited severely compromised kidney function. Low-vacuum scanning electron microscopy revealed excessive calcium (Ca) deposition in the outer medulla of Tl-loaded rats, particularly in the medullary thick ascending limb (mTAL) of the loop of Henle. Tl accumulated in the mTAL, accompanied by mitochondrial dysfunction in this segment. Tl-loaded rats showed reduced expression of kidney transporters and channels responsible for Ca2+ reabsorption in the mTAL. Pre-administration of the Na–K–Cl cotransporter 2 (NKCC2) inhibitor furosemide alleviated Tl accumulation and mitochondrial abnormalities in the mTAL. These findings suggest that Tl nephrotoxicity is associated with preferential Tl reabsorption in the mTAL via NKCC2, leading to mTAL mitochondrial dysfunction and disrupted Ca2+ reabsorption, culminating in mTAL-predominant Ca crystal deposition and AKI. These findings on the mechanism of Tl nephrotoxicity may contribute to the development of novel therapeutic approaches to counter Tl poisoning. Moreover, the observation of characteristic Ca crystal deposition in the outer medulla provides new insights into diagnostic challenges in Tl intoxication.

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来源期刊
Archives of Toxicology
Archives of Toxicology 医学-毒理学
CiteScore
11.60
自引率
4.90%
发文量
218
审稿时长
1.5 months
期刊介绍: Archives of Toxicology provides up-to-date information on the latest advances in toxicology. The journal places particular emphasis on studies relating to defined effects of chemicals and mechanisms of toxicity, including toxic activities at the molecular level, in humans and experimental animals. Coverage includes new insights into analysis and toxicokinetics and into forensic toxicology. Review articles of general interest to toxicologists are an additional important feature of the journal.
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