Met-RANTES reduces endothelial progenitor cell homing to activated (glomerular) endothelium in vitro and in vivo.
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.
Rookmaaker
Maarten B
MB
Dept. of Vascular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
Verhaar
Marianne C
MC
de Boer
Hetty C
HC
Goldschmeding
Roel
R
Joles
Jaap A
JA
Koomans
Hein A
HA
Gröne
Hermann-Josef
HJ
Rabelink
Ton J
TJ
D000818:Animals; D000911:Antibodies, Monoclonal; D018952:Antigens, CD34 / Q000097:blood / Q000235:genetics; D018946:Chemokine CCL5 / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects*; D004727:Endothelium / Q000166:cytology / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D005921:Glomerulonephritis / Q000139:chemically induced / Q000473:pathology; D007668:Kidney / Q000473:pathology; D007678:Kidney Glomerulus / Q000166:cytology* / Q000187:drug effects; D008297:Male; D051381:Rats; D011914:Rats, Inbred BN; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000187:drug effects*; D018800:Thy-1 Antigens / Q000276:immunology
D000911:Antibodies, Monoclonal; D018952:Antigens, CD34; D018946:Chemokine CCL5; C108335:RANTES, Met-; D018800:Thy-1 Antigens