Inhibition of sphingosine 1-phosphate receptor 2 protects against renal ischemia-reperfusion injury.
Inhibition of sphingosine 1-phosphate receptor 2 protects against renal ischemia-reperfusion injury.
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DOI：
10.1681/asn.2011050503
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发表时间：
2012-02
期刊：
影响因子：
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通讯作者：
Sang-Won Park;Mihwa Kim;K. Brown;D. VivetteD.;Agati;H. Lee
中科院分区：
文献类型：
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作者：
Sang-Won Park;Mihwa Kim;K. Brown;D. VivetteD.;Agati;H. Lee
1-磷酸鞘氨醇受体 1 (S1P(1)R) 的激活可防止肾缺血再灌注 (IR) 损伤和炎症，但该受体家族的其他成员在调节肾 IR 损伤中的作用尚不清楚。我们发现选择性 S1P(2)R 拮抗剂以剂量依赖性方式预防肾 IR 损伤。与这一观察结果一致，S1P(2)R 缺陷型小鼠和用 S1P(2)R 小干扰 RNA 治疗的野生型小鼠在 IR 后肾损伤均减轻。相反，选择性S1P(2)R激动剂会加剧肾IR损伤。 S1P(2)R 拮抗剂通过肾近曲小管中的 Rho 激酶信号传导增加鞘氨醇激酶 1 (SK1) 的表达； S1P(2)R 激动剂降低 SK1。 S1P(2)R 拮抗作用无法保护 SK1 缺陷小鼠或用 SK1 抑制剂或 S1P(1)R 拮抗剂预处理的野生型小鼠的肾脏，这表明 S1P(2)R 拮抗作用所赋予的肾脏保护作用是由涉及 SK1 激活 S1P(1)R 的途径引起的。在培养的人近曲小管 (HK-2) 细胞中，S1P(2)R 拮抗剂选择性上调 SK1 并减弱 H(2)O(2) 诱导的坏死和 TNF-α/放线菌酮诱导的细胞凋亡。 S1P(2)R 激动剂具有相反的作用。此外，核缺氧诱导因子1α的增加对于介导S1P(2)R抑制的肾脏保护作用至关重要。最后，肾IR和S1P(2)R拮抗作用引起的SK1和S1P(2)R的诱导选择性地发生在肾近曲小管细胞中，但不发生在肾内皮细胞中。综上所述，这些数据表明 S1P(2)R 可能是减轻肾 IR 损伤影响的治疗靶点。
Activation of the sphingosine 1-phosphate receptor 1 (S1P(1)R) protects against renal ischemia-reperfusion (IR) injury and inflammation, but the role of other members of this receptor family in modulating renal IR injury is unknown. We found that a selective S1P(2)R antagonist protected against renal IR injury in a dose-dependent manner. Consistent with this observation, both S1P(2)R-deficient mice and wild-type mice treated with S1P(2)R small interfering RNA had reduced renal injury after IR. In contrast, a selective S1P(2)R agonist exacerbated renal IR injury. The S1P(2)R antagonist increased sphingosine kinase-1 (SK1) expression via Rho kinase signaling in renal proximal tubules; the S1P(2)R agonist decreased SK1. S1P(2)R antagonism failed to protect the kidneys of SK1-deficient mice or wild-type mice pretreated with an SK1 inhibitor or an S1P(1)R antagonist, suggesting that the renoprotection conferred by S1P(2)R antagonism results from pathways involving activation of S1P(1)R by SK1. In cultured human proximal tubule (HK-2) cells, the S1P(2)R antagonist selectively upregulated SK1 and attenuated both H(2)O(2)-induced necrosis and TNF-α/cycloheximide-induced apoptosis; the S1P(2)R agonist had the opposite effects. In addition, increased nuclear hypoxia inducible factor-1α was critical in mediating the renoprotective effects of S1P(2)R inhibition. Finally, induction of SK1 and S1P(2)R in response to renal IR and S1P(2)R antagonism occurred selectively in renal proximal tubule cells but not in renal endothelial cells. Taken together, these data suggest that S1P(2)R may be a therapeutic target to attenuate the effects of renal IR injury.