Depleted uranium causes renal mitochondrial dysfunction through the ETHE1/Nrf2 pathway

Liu, Suiyi; Wang, Shuang; Zhao, Yazhen; Li, Juan; Shu, Chang; Li, Yong; Li, Jie; Lu, Binghui; Xu, Zeheng; Ran, Yonghong; Hao, Yuhui

doi:10.1016/j.cbi.2023.110356

Cited by 7 publications

(1 citation statement)

References 51 publications

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“…The kidney is a key organ in maintaining ion and fluid homeostasis, eliminating metabolic degradation products. Besides, kidney and more specifically the tubular epithelial cells were reported as the primary target for the chemical toxicity of DU, ending with renal dysfunction and damage of the tubular cells 7,8 . For example, Hao et al demonstrated that DU could induce cytotoxicity towards HEK‐293 T cells by activating nucleus p53 and inhibiting mTOR signal 9 .…”

Section: Introductionmentioning

confidence: 99%

Hedgehog pathway negatively regulated depleted uranium‐induced nephrotoxicity

Xie,

Fu,

Liu

et al. 2024

Environmental Toxicology

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Depleted uranium (DU) retains the radiological toxicities, which accumulates preferentially in the kidneys. Hedgehog (Hh) pathway plays a critical role in tissue injury. However, the role of Hh in DU‐induced nephrotoxicity was still unclear. This study was carried out to investigate the effect of Gli2, which was an important transcription effector of Hh signaling, on DU induced nephrotoxicity. To clarify it, CK19 positive tubular epithelial cells specific Gli2 conditional knockout (KO) mice model was exposed to DU, and then histopathological damage and Hh signaling pathway activation was analyzed. Moreover, HEK‐293 T cells were exposed to DU with Gant61 or Gli2 overexpression, and cytotoxicity of DU as analyzed. Results showed that DU caused nephrotoxicity accompanied by activation of Hh signaling pathway. Meanwhile, genetic KO of Gli2 reduced DU‐induced nephrotoxicity by normalizing biochemical indicators and reducing Hh pathway activation. Pharmacologic inhibition of Gli1/2 by Gant61 reduced DU induced cytotoxicity by inhibiting apoptosis, ROS formation and Hh pathway activation. However, overexpression of Gli2 aggravated DU‐induced cytotoxicity by increasing the levels of apoptosis and ROS formation. Taken together, these results revealed that Hh signaling negatively regulated DU‐inducted nephrotoxicity, and that inhibition of Gli2 might serve as a promising nephroprotective target for DU‐induced kidney injury.

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Section: Introductionmentioning

confidence: 99%