Martini Sebastian, Krämer Stephanie, Loof Tanja, Wang-Rosenke Yingrui, Daig Ute, Budde Klemens, Neumayer Hans-H, Peters Harm
Department of Nephrology, Charité Universitätsmedizin Berlin, Charité Campus Mitte, Humboldt University, Berlin, Germany.
Am J Physiol Renal Physiol. 2007 Jun;292(6):F1761-70. doi: 10.1152/ajprenal.00253.2006. Epub 2007 Mar 13.
FTY720 is a novel immune modulator whose primary action is blood lymphocyte depletion through interaction with sphingosine-1-phosphate (S1P) receptors. The present study analyzes the effect of FTY720 on both the early mesangial cell injury and the subsequent matrix expansion phase of experimental mesangioproliferative glomerulonephritis. Disease was induced by injection of OX-7 anti-thy1 antibody into male Wistar rats. In both protocols, FTY720 administration (0.3 mg/kg body wt) resulted in a selective and very marked reduction in blood lymphocyte count. In the injury experiment, the S1P receptor modulator was given starting 5 days before and continued until 1 day after antibody injection. FTY720 did not significantly affect the degree of anti-thy1-induced mesangial cell lysis and glomerular-inducible nitric oxide production. In the matrix expansion experiment, FTY720 treatment was started 1 day after antibody injection and continued until day 7. In this protocol, the S1P modulator reduced proteinuria, histological matrix expansion, and glomerular protein expression of TGF-beta(1), fibronectin, and PAI-1. Glomerular collagen III staining intensity was decreased. FTY720 reduced markedly glomerular lymphocyte number per cross section and to a lesser degree macrophage infiltration. In conclusion, FTY720 significantly limits TGF-beta(1) overexpression and matrix protein expression following induction of acute anti-thy glomerulonephritis, involving reductions in blood and glomerular lymphocyte numbers. The results suggest that lymphocytes actively contribute to matrix expansion in experimental mesangioproliferative glomerulonephritis. Our study expands on findings on FTY720's beneficial effects on tubulointerstitial and functional disease progression previously reported in anti-thy1-induced chronic glomerulosclerosis.
FTY720是一种新型免疫调节剂，其主要作用是通过与1-磷酸鞘氨醇（S1P）受体相互作用使血液淋巴细胞耗竭。本研究分析了FTY720对实验性系膜增生性肾小球肾炎早期系膜细胞损伤及随后的基质扩张期的影响。通过向雄性Wistar大鼠注射OX-7抗Thy1抗体诱导疾病。在两个实验方案中，给予FTY720（0.3mg/kg体重）导致血液淋巴细胞计数选择性且非常显著地降低。在损伤实验中，在抗体注射前5天开始给予S1P受体调节剂，并持续至抗体注射后1天。FTY720对抗Thy1诱导的系膜细胞溶解程度和肾小球诱导型一氧化氮产生无显著影响。在基质扩张实验中，在抗体注射后1天开始FTY720治疗，并持续至第7天。在该实验方案中，S1P调节剂降低了蛋白尿、组织学基质扩张以及TGF-β1、纤连蛋白和PAI-1的肾小球蛋白表达。肾小球Ⅲ型胶原染色强度降低。FTY720显著减少了每个横截面的肾小球淋巴细胞数量，并在较小程度上减少了巨噬细胞浸润。总之，FTY720在急性抗Thy肾小球肾炎诱导后显著限制TGF-β1过表达和基质蛋白表达，这涉及血液和肾小球淋巴细胞数量的减少。结果表明淋巴细胞在实验性系膜增生性肾小球肾炎的基质扩张中起积极作用。我们的研究扩展了先前报道的FTY720对抗Thy1诱导的慢性肾小球硬化症肾小管间质和功能疾病进展有益作用的研究结果。
