Xie Xueying, Fu Guoquan, Liu Yuxin, Fan Caixia, Tan Shanshan, Huang Huarong, Yan Junyan, Jin Lifang
School of Life and Environmental Sciences, Shaoxing University, Shaoxing, Zhejiang, China.
College of Life and Environmental Science, Hangzhou Normal University, Hangzhou, China.
Environ Toxicol. 2024 Jul;39(7):3833-3845. doi: 10.1002/tox.24242. Epub 2024 Mar 28.
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.
贫铀（DU）具有放射性毒性，且优先在肾脏中蓄积。刺猬信号通路（Hh）在组织损伤中起关键作用。然而，Hh在DU诱导的肾毒性中的作用仍不清楚。本研究旨在探讨Gli2（Hh信号的重要转录效应因子）对DU诱导的肾毒性的影响。为阐明这一点，将细胞角蛋白19（CK19）阳性肾小管上皮细胞特异性Gli2条件性敲除（KO）小鼠模型暴露于DU，然后分析组织病理学损伤和Hh信号通路激活情况。此外，将人胚肾细胞293T（HEK-293 T）细胞暴露于DU并添加Gant61或进行Gli2过表达，分析DU的细胞毒性。结果显示，DU导致肾毒性并伴有Hh信号通路激活。同时，Gli2基因敲除通过使生化指标正常化并减少Hh通路激活减轻了DU诱导的肾毒性。Gant61对Gli1/2的药理学抑制通过抑制细胞凋亡、活性氧（ROS）形成和Hh通路激活降低了DU诱导的细胞毒性。然而，Gli2过表达通过增加细胞凋亡水平和ROS形成加剧了DU诱导的细胞毒性。综上所述，这些结果表明Hh信号负向调节DU诱导的肾毒性，抑制Gli2可能是DU诱导的肾损伤有前景的肾保护靶点。
