Sphingosine 1-Phosphate Receptor-1 Enhances Mitochondrial Function and Reduces Cisplatin-Induced Tubule Injury
Sphingosine 1-Phosphate Receptor-1 Enhances Mitochondrial Function and Reduces Cisplatin-Induced Tubule Injury
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DOI：
10.1681/asn.2013121351
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发表时间：
2015-04-01
影响因子：
13.6
通讯作者：
Okusa, Mark D.
中科院分区：
文献类型：
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作者：
Bajwa, Amandeep;Rosin, Diane L.;Okusa, Mark D.
鞘氨醇1-磷酸(S1P)是五种G蛋白偶联受体(S1P1-S1P5Rs)家族的天然鞘磷脂配体，调节细胞存活和淋巴细胞循环。我们已经证明，PAN-S1PR激动剂FTY720通过直接激活近端小管(PT)细胞上的S1P1来减轻肾脏缺血再灌注损伤，而不依赖于S1P1激活对B细胞和T细胞的典型的淋巴细胞减少效应。FTY720还可减少顺铂诱导的AKI。因此，在本研究中，我们利用条件性PT-S1P1-Null(PepckCreS1pr1(fl/fl))小鼠和对照(Pepck CreS1pr1(w/wt))小鼠来确定FTY720在AKI中的保护作用是否由PT-S1P1介导。顺铂对PT-S1P1基因缺失小鼠的肾脏损伤程度高于对照组。尽管FTY720在对照组和PT-S1P1缺失的小鼠中都产生了淋巴细胞减少，但它只在对照组小鼠中减少了损伤。此外，FTY720可抑制顺铂诱导的促炎细胞因子(CXCL1、MCP-1、TNF-α和IL-6)的表达增加以及中性粒细胞和巨噬细胞的浸润，但对PT-S1P1基因缺失的小鼠没有影响。同样，S1P1缺失使培养的PT细胞对顺铂诱导的损伤更敏感，而S1P1过表达则保护PT细胞免受损伤，并保留线粒体功能。我们得出结论，S1P1在稳定线粒体功能方面可能具有重要作用，FTY720给药代表了预防顺铂诱导的AKI的一种新策略。
Sphingosine 1-phosphate (S1P), the natural sphingolipid ligand for a family of five G protein-coupled receptors (S1P1-S1P5Rs), regulates cell survival and lymphocyte circulation. We have shown that the pan-S1PR agonist, FTY720, attenuates kidney ischemia-reperfusion injury by directly activating S1P1 on proximal tubule (PT) cells, independent of the canonical lymphopenic effects of S1P1 activation on B and T cells. FTY720 also reduces cisplatin-induced AKI. Therefore, in this study, we used conditional PT-S1P1-null (PepckCreS1pr1(fl/fl)) and control (PepckCreS1pr1(w/wt)) mice to determine whether the protective effect of FTY720 in AKI is mediated by PT-S1P1. Cisplatin induced more renal injury in PT-S1P1-null mice than in controls. Although FTY720 produced lymphopenia in both control and PT-S1P1-null mice, it reduced injury only in control mice. Furthermore, the increase in proinflammatory cytokine (CXCL1, MCP-1, TNF-alpha, and IL-6) expression and infiltration of neutrophils and macrophages induced by cisplatin treatment was attenuated by FTY720 in control mice but not in PT-S1P1-null mice. Similarly, S1P1 deletion rendered cultured PT cells more susceptible to cisplatin-induced injury, whereas S1P1 overexpression protected PT cells from injury and preserved mitochondrial function. We conclude that S1P1 may have an important role in stabilizing mitochondrial function and that FTY720 administration represents a novel strategy in the prevention-of cisplatin-induced AKI.