Awad Alaa S, Ye Hong, Huang Liping, Li Li, Foss Frank W, Macdonald Timothy L, Lynch Kevin R, Okusa Mark D
Department of Medicine, Univ. of Virginia, Charlottesville, VA, USA.
Am J Physiol Renal Physiol. 2006 Jun;290(6):F1516-24. doi: 10.1152/ajprenal.00311.2005. Epub 2006 Jan 10.
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 S1P1 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 approximately 73 and approximately 69% with doses of 240 and 48 microg/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 S1P1 receptor antagonist. Furthermore, SEW-2871, a selective S1P1 agonist, significantly decreased plasma creatinine in a dose-response manner with a maximal reduction of approximately 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 S1P1 mRNA expression following IRI that begins after 2 h with the maximum expression at approximately 4 h. We conclude that the protective effect of FTY-720 is due primarily to activation of S1P1 receptors. The mechanism of protection is not known but may be related to peripheral lymphocyte depletion or direct effects on kidney cells expressing S1P1 receptor.
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）可诱导外周T细胞耗竭。因此，我们推测S1P1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，然后对动物进行32分钟的缺血，随后再灌注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，分别给予240和48μg/kg剂量时，最大降幅约为73%和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S1P1受体拮抗剂VPC-44116可逆转FTY-720的保护作用。此外，选择性S1P1激动剂SEW-2871以剂量反应方式显著降低血浆肌酐，给予10mg/kg剂量时最大降幅约为70%。与载体组相比，用FTY-720或SEW-2871治疗后，通过光学显微镜分析肾脏发现缺血损伤的组织学迹象最小。使用逆转录聚合酶链反应（RT-PCR），我们发现IRI后S1P1 mRNA表达呈时间依赖性增加，在2小时后开始，约4小时达到最大表达。我们得出结论，FTY-720的保护作用主要归因于S1P1受体的激活。保护机制尚不清楚，但可能与外周淋巴细胞耗竭或对表达S1P1受体的肾细胞的直接作用有关。
