de Assis Juliane Lopes, Grelle Gloria Maria Ramalho Soares, Fernandes Aline Marie, da Silva Aniceto Bárbara, Pompeu Pedro, de Mello Fabiana Vieira, Garrett Rafael, Valverde Rafael Hospodar Felippe, Einicker-Lamas Marcelo
Laboratório de Biomembranas, Instituto de Biofísica Carlos Chagas Filho - Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Laboratório de Metabolômica, LADETEC, Instituto de Química - Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
J Physiol Biochem. 2024 Nov;80(4):831-843. doi: 10.1007/s13105-024-01038-7. Epub 2024 Aug 19.
Acute kidney injury is a serious public health problem worldwide, being ischemia and reperfusion (I/R) the main lesion-aggravating factor that contributes to the evolution towards chronic kidney disease. Nonetheless, intervention approaches currently available are just considered palliative options. In order to offer an alternative treatment, it is important to understand key factors involved in the development of the disease including the rescue of the affected cells and/or the release of paracrine factors that are crucial for tissue repair. Bioactive lipids such as sphingosine 1-phosphate (S1P) have significant effects on the modulation of signaling pathways involved in tissue regeneration, such as cell survival, proliferation, differentiation, and migration. The main objective of this work was to explore the protective effect of S1P using human kidney proximal tubule cells submitted to a mimetic I/R lesion, via ATP depletion. We observed that the S1P pre-treatment increases cell survival by 50% and preserves the cell proliferation capacity of injured cells. We showed the presence of different bioactive lipids notably related to tissue repair but, more importantly, we noted that the pre-treatment with S1P attenuated the ischemia-induced effects in response to the injury, resulting in higher endogenous S1P production. All receptors but S1PR3 are present in these cells and the protective and proliferative effect of S1P/S1P receptors axis occur, at least in part, through the activation of the SAFE pathway. To our knowledge, this is the first time that S1PR4 and S1PR5 are referred in these cells and also the first indication of JAK2/STAT3 pathway involvement in S1P-mediated protection in an I/R renal model.
急性肾损伤是一个全球性的严重公共卫生问题，缺血再灌注（I/R）是导致其向慢性肾病发展的主要损伤加重因素。尽管如此，目前可用的干预方法仅被视为姑息性选择。为了提供一种替代治疗方法，了解该疾病发展过程中的关键因素非常重要，包括挽救受影响的细胞和/或释放对组织修复至关重要的旁分泌因子。生物活性脂质如1-磷酸鞘氨醇（S1P）对参与组织再生的信号通路调节具有显著影响，如细胞存活、增殖、分化和迁移。这项工作的主要目的是通过ATP耗竭，利用遭受模拟I/R损伤的人肾近端小管细胞来探索S1P的保护作用。我们观察到，S1P预处理可使细胞存活率提高50%，并保留受损细胞的增殖能力。我们发现存在与组织修复显著相关的不同生物活性脂质，但更重要的是，我们注意到S1P预处理减弱了损伤后缺血诱导的效应，导致内源性S1P产生增加。除S1PR3外，所有受体均存在于这些细胞中，S1P/S1P受体轴的保护和增殖作用至少部分是通过SAFE途径的激活实现的。据我们所知，这是首次在这些细胞中提及S1PR4和S1PR5，也是首次表明JAK2/STAT3通路参与I/R肾模型中S1P介导的保护作用。
