Selective sphingosine 1-phosphate 1 receptor activation reduces ischemia-reperfusion injury in mouse kidney
Selective sphingosine 1-phosphate 1 receptor activation reduces ischemia-reperfusion injury in mouse kidney
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DOI：
10.1152/ajprenal.00311.2005
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发表时间：
2006-06-01
影响因子：
4.2
通讯作者：
Okusa, MD
中科院分区：
文献类型：
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作者：
Awad, AS;Ye, H;Okusa, MD
肾缺血再灌注损伤（IRI）所涉及的机制很复杂，似乎涉及骨髓来源细胞的早期参与。T淋巴细胞参与IRI的发病机制。1 - 磷酸鞘氨醇（S1P）诱导外周T细胞耗竭。因此，我们假设S1P（1）受体激活可保护肾脏免受IRI损伤。将非受体选择性鞘氨醇类似物FTY - 720腹腔注射给C57BL / 6小鼠，使动物缺血32分钟，然后再灌注24小时。测定血浆肌酐、血细胞计数、髓过氧化物酶（MPO）活性和肾脏组织学。IRI导致血浆肌酐、MPO活性、白细胞浸润和血管通透性显著增加。FTY - 720以剂量 - 反应方式显著降低血浆肌酐，在剂量为240μg/kg和48μg/kg时，最大降幅分别约为73%和约69%。FTY - 720治疗可显著降低MPO、白细胞浸润、血管通透性和外周血淋巴细胞计数。选择性S1P（1）受体拮抗剂VPC - 44116可逆转FTY - 720的保护作用。此外，选择性S1P（1）激动剂SEW - 2871以剂量 - 反应方式显著降低血浆肌酐，在剂量为10mg/kg时最大降幅约为70%。光镜下对肾脏的分析显示，与溶媒组相比，FTY - 720或SEW - 2871治疗组缺血性损伤的组织学迹象极小。通过逆转录 - 聚合酶链反应（RT - PCR），我们发现IRI后S1P（1）mRNA表达呈时间依赖性增加，在2小时后开始，约4小时时表达最高。我们得出结论，FTY - 720的保护作用主要是由于S1P（1）受体的激活。其保护机制尚不清楚，但可能与外周淋巴细胞耗竭或对表达S1P（1）受体的肾细胞的直接作用有关。
The mechanisms involved in renal ischemia-reperfusion injury (IRI) are complex and appear to involve the early participation of bone marrow-derived cells. T lymphocytes participate in the pathogenesis of IRI. Sphingosine 1-phosphate (S1P) induces peripheral T cell depletion. Therefore, we hypothesized that S1P(1) receptor activation protects kidney from IRI. FTY-720, a non-receptor-selective sphingosine analog, was given intraperitoneally to C57BL/6 mice, and animals were subjected to ischemia for 32 min followed by reperfusion for 24 h. Plasma creatinine, blood count, myeloperoxidase (MPO) activity, and renal histology were determined. IRI led to a marked increase in plasma creatinine, MPO activity, leukocyte infiltration, and vascular permeability. FTY-720 significantly decreased plasma creatinine in a dose-response manner with a maximal reduction of similar to 73 and similar to 69% with doses of 240 and 48 mu g/kg, respectively. MPO, leukocyte infiltration, vascular permeability, and peripheral blood lymphocyte counts were markedly decreased with FTY-720 treatment. The protective effect of FTY-720 was reversed with VPC-44116, a selective S1P(1) receptor antagonist. Furthermore, SEW-2871, a selective S1P(1) agonist, significantly decreased plasma creatinine in a dose-response manner with a maximal reduction of similar to 70% with a dose of 10 mg/kg. Analysis of kidneys by light microscopy revealed minimal histological signs of ischemic injury with FTY-720 or SEW-2871 treatment compared with the vehicle group. Using RT-PCR, we found a time-dependent increase in the S1P(1) mRNA expression following IRI that begins after 2 h with the maximum expression at similar to 4 h. We conclude that the protective effect of FTY-720 is due primarily to activation of S1P(1) receptors. The mechanism of protection is not known but may be related to peripheral lymphocyte depletion or direct effects on kidney cells expressing S1P(1) receptor.