Department of Endocrinology and Diabetes, Yamanashi Prefectural Central Hospital, Fujimi 1-1-1, Kofu, Japan.
Division of Oxygen Biology, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Seiryo-machi 2-1, Aoba-ku, Sendai, Japan.
Int J Mol Sci. 2020 Apr 22;21(8):2951. doi: 10.3390/ijms21082951.
Over 10% of the global population suffers from kidney disease. However, only kidney replacement therapies, which burden medical expenses, are currently effective in treating kidney disease. Therefore, elucidating the complicated molecular pathology of kidney disease is an urgent priority for developing innovative therapeutics for kidney disease. Recent studies demonstrated that intertwined renal vasculature often causes ischemia-reperfusion injury (IRI), which generates oxidative stress, and that the accumulation of oxidative stress is a common pathway underlying various types of kidney disease. We reported that activating the antioxidative transcription factor Nrf2 in renal tubules in mice with renal IRI effectively mitigates tubular damage and interstitial fibrosis by inducing the expression of genes related to cytoprotection against oxidative stress. Additionally, since the kidney performs multiple functions beyond blood purification, renoprotection by Nrf2 activation is anticipated to lead to various benefits. Indeed, our experiments indicated the possibility that Nrf2 activation mitigates anemia, which is caused by impaired production of the erythroid growth factor erythropoietin from injured kidneys, and moderates organ damage worsened by anemic hypoxia. Clinical trials investigating Nrf2-activating compounds in kidney disease patients are ongoing, and beneficial effects are being obtained. Thus, Nrf2 activators are expected to emerge as first-in-class innovative medicine for kidney disease treatment.
全球有超过 10%的人口患有肾脏疾病。然而，目前只有肾脏替代疗法对肾脏疾病有效，而这种疗法会增加医疗费用。因此，阐明肾脏疾病复杂的分子病理学机制是开发肾脏疾病创新疗法的当务之急。最近的研究表明，肾脏血管的交织往往会导致缺血再灌注损伤（IRI），从而产生氧化应激，而氧化应激的积累是各种类型肾脏疾病的共同途径。我们曾报道，在肾脏 IRI 模型小鼠的肾小管中激活抗氧化转录因子 Nrf2，可通过诱导与抗氧化应激相关的保护性基因表达，有效减轻肾小管损伤和间质纤维化。此外，由于肾脏具有除血液净化以外的多种功能，因此预计 Nrf2 激活的肾脏保护作用将带来各种益处。事实上，我们的实验表明，Nrf2 激活具有减轻贫血的可能性，这种贫血是由受损肾脏产生的促红细胞生成素（erythropoietin）减少引起的，并且可以减轻贫血性缺氧引起的器官损伤恶化。目前正在进行针对肾脏疾病患者的 Nrf2 激活化合物的临床试验，并已获得有益的效果。因此，Nrf2 激活剂有望成为治疗肾脏疾病的首创创新药物。
