Rookmaaker Maarten B, Verhaar Marianne C, de Boer Hetty C, Goldschmeding Roel, Joles Jaap A, Koomans Hein A, Gröne Hermann-Josef, Rabelink Ton J
Dept. of Vascular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
Am J Physiol Renal Physiol. 2007 Aug;293(2):F624-30. doi: 10.1152/ajprenal.00398.2006. Epub 2007 Jun 13.
The chemokine RANTES (regulated upon activation normal T-cell expressed and secreted) is involved in the formation of an inflammatory infiltrate during glomerulonephritis. However, RANTES receptor inhibition, although reducing glomerular leukocyte infiltration, can also increase damage. We hypothesized that RANTES does not only promote the influx and activation of inflammatory leukocytes but also mediates glomerular microvascular repair by stimulating the homing of bone marrow (BM)-derived endothelial progenitor cells. To investigate the role of RANTES in the participation of BM-derived cells in glomerular vascular repair, we used a rat BM transplantation model in combination with reversible anti-Thy-1.1 glomerulonephritis. Twenty-four hours after the induction of glomerulonephritis, BM-transplanted rats were treated for 7 days with either the RANTES receptor antagonist Met-RANTES or saline. The participation of BM-derived endothelial cells in glomerular repair, glomerular monocyte infiltration, and proteinuria was evaluated at days 7 and 28. Furthermore, we used an in vitro perfusion chamber assay to study the role of RANTES receptors in shear-resistant adhesion of the CD34+ stem cells to activated endothelium under flow. In our reversible glomerulonephritis model, RANTES receptor inhibition specifically reduced the participation of BM-derived cells in glomerular vascular repair by more than 40% at day 7 without impairing monocyte influx. However, no obvious change in recovery from proteinuria or morphological damage was observed. Blockade of RANTES receptors on CD34+ cells in vitro partially inhibited platelet-enhanced, shear-resistant firm adhesion of the CD34+ cells to activated endothelium. In conclusion, our data suggest that RANTES is involved in the homing and participation of BM-derived endothelial cells in glomerular repair.
趋化因子RANTES（活化时正常T细胞表达和分泌的调节因子）参与肾小球肾炎期间炎性浸润的形成。然而，抑制RANTES受体虽然可减少肾小球白细胞浸润，但也会增加损伤。我们推测RANTES不仅促进炎性白细胞的流入和活化，还通过刺激骨髓（BM）来源的内皮祖细胞归巢来介导肾小球微血管修复。为了研究RANTES在BM来源细胞参与肾小球血管修复中的作用，我们将大鼠BM移植模型与可逆性抗Thy-1.1肾小球肾炎相结合。诱导肾小球肾炎24小时后，对接受BM移植的大鼠用RANTES受体拮抗剂Met-RANTES或生理盐水治疗7天。在第7天和第28天评估BM来源的内皮细胞参与肾小球修复、肾小球单核细胞浸润和蛋白尿的情况。此外，我们使用体外灌注室试验来研究RANTES受体在流动条件下CD34+干细胞与活化内皮的抗剪切黏附中的作用。在我们的可逆性肾小球肾炎模型中，抑制RANTES受体在第7天时特异性地减少了BM来源细胞参与肾小球血管修复的比例超过40%，而不影响单核细胞流入。然而，未观察到蛋白尿恢复或形态学损伤有明显变化。体外阻断CD34+细胞上的RANTES受体可部分抑制血小板增强的、抗剪切的CD34+细胞与活化内皮的牢固黏附。总之，我们的数据表明RANTES参与BM来源的内皮细胞归巢和参与肾小球修复。
