Kana Unuma, Shuheng Wen, Sho Sugahara, Shutaro Nagano, Toshihiko Aki, Tadayuki Ogawa, Shino Takeda-Homma, Masakazu Oikawa, Akihiro Tojo
Archives of toxicology 2024 DecThallium (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. © 2024. The Author(s).
Kana Unuma, Shuheng Wen, Sho Sugahara, Shutaro Nagano, Toshihiko Aki, Tadayuki Ogawa, Shino Takeda-Homma, Masakazu Oikawa, Akihiro Tojo. Thallium reabsorption via NKCC2 causes severe acute kidney injury with outer medulla-specific calcium crystal casts in rats. Archives of toxicology. 2024 Dec;98(12):3973-3986
PMID: 39361050
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