Department of Emergency, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou 570311, Hainan, China.
Hunan Yuantai Biotechnology Co., Ltd, Changsha 410000, Hunan, China.
Aging (Albany NY). 2021 Jan 20;13(3):4452-4467. doi: 10.18632/aging.202406.
Paraquat poisoning causes lung fibrosis, which often results in long-term pulmonary dysfunction. Lung fibrosis has been attributed to collagens accumulation, but the underlying regulatory pathway remains unclear. Here we use the genetically tractable as a model to study collagen gene transcription in response to paraquat. We find that paraquat robustly up-regulates collagen gene transcription, which is dependent on KRI-1, a poorly studied protein homologous to human KRIT1/CCM1. KRI-1 knockdown prevents paraquat from activating the oxidative stress response transcription factor SKN-1/Nrf2, resulting in reduced collagen transcription and increased paraquat sensitivity. Using human lung fibroblasts (MRC-5), we confirm that both KRIT1 and Nrf2 are required for collagen transcription in response to paraquat. Nrf2 hyper-activation by KEAP1 knockdown bypasses KRIT1 to up-regulate collagen transcription. Our findings on the regulation of collagen gene transcription by paraquat could suggest potential strategies to treat pulmonary fibrosis caused by paraquat poisoning.
百草枯中毒会导致肺纤维化，常导致长期的肺功能障碍。肺纤维化归因于胶原的积累，但潜在的调控途径尚不清楚。在这里，我们使用遗传上可操作的秀丽隐杆线虫作为模型，研究百草枯对胶原基因转录的影响。我们发现百草枯能强烈地上调胶原基因的转录，这依赖于 KRIT1，一种与人类 KRIT1/CCM1 同源的研究甚少的蛋白。KRIT1 的敲低阻止百草枯激活氧化应激反应转录因子 SKN-1/Nrf2，导致胶原转录减少和百草枯敏感性增加。使用人肺成纤维细胞 (MRC-5)，我们证实 KRIT1 和 Nrf2 都需要参与百草枯诱导的胶原转录。KEAP1 敲低导致 Nrf2 的过度激活，绕过 KRIT1 而上调胶原转录。我们关于百草枯调控胶原基因转录的发现，可能为治疗百草枯中毒引起的肺纤维化提供潜在策略。
