Department of Medicine, Division of Nephrology, Box 800133, University of Virginia Health System, Charlottesville, VA 22908, USA.
J Am Soc Nephrol. 2010 Jun;21(6):955-65. doi: 10.1681/ASN.2009060662. Epub 2010 Mar 25.
Agonists of the sphingosine-1-phosphate receptor (S1PR) attenuate kidney ischemia-reperfusion injury (IRI). Previous studies suggested that S1P1R-induced lymphopenia mediates this protective effect, but lymphocyte-independent mechanisms could also contribute. Here, we investigated the effects of S1PR agonists on kidney IRI in mice that lack T and B lymphocytes (Rag-1 knockout mice). Administration of the nonselective S1PR agonist FTY720 or the selective S1P1R agonist SEW2871 reduced injury in both Rag-1 knockout and wild-type mice. In vitro, SEW2871 significantly attenuated LPS- or hypoxia/reoxygenation-induced apoptosis in cultured mouse proximal tubule epithelial cells, supporting a direct protective effect of S1P1R agonists via mitogen-activated protein kinase and/or Akt pathways. S1P1Rs in the proximal tubule mediated IRI in vivo as well: Mice deficient in proximal tubule S1P1Rs experienced a greater decline in renal function after IRI than control mice and their kidneys were no longer protected by SEW2871 administration. In summary, S1PRs in the proximal tubule are necessary for stress-induced cell survival, and S1P1R agonists are renoprotective via direct effects on the tubule cells. Selective agonists of S1P1Rs may hold therapeutic potential for the prevention and treatment of acute kidney injury.
鞘氨醇-1-磷酸受体（S1PR）激动剂可减轻肾缺血再灌注损伤（IRI）。先前的研究表明，S1P1R 诱导的淋巴细胞减少介导了这种保护作用，但也可能存在非淋巴细胞依赖性机制。在这里，我们研究了 S1PR 激动剂对缺乏 T 和 B 淋巴细胞的小鼠（Rag-1 敲除小鼠）肾 IRI 的影响。非选择性 S1PR 激动剂 FTY720 或选择性 S1P1R 激动剂 SEW2871 的给药均减轻了 Rag-1 敲除和野生型小鼠的损伤。在体外，SEW2871 显著减轻了 LPS 或缺氧/复氧诱导的培养的小鼠近端肾小管上皮细胞凋亡，支持 S1P1R 激动剂通过丝裂原活化蛋白激酶和/或 Akt 途径发挥直接保护作用。近端肾小管中的 S1P1Rs 也介导了体内的 IRI：与对照小鼠相比，近端肾小管 S1P1Rs 缺失的小鼠在 IRI 后肾功能下降更明显，并且它们的肾脏不再受到 SEW2871 给药的保护。总之，近端肾小管中的 S1PRs 是应激诱导细胞存活所必需的，而 S1P1R 激动剂通过对肾小管细胞的直接作用具有肾脏保护作用。S1P1Rs 的选择性激动剂可能具有预防和治疗急性肾损伤的治疗潜力。
