Antagonism of PDGF-D by human antibody CR002 prevents renal scarring in experimental glomerulonephritis.
Glomerular mesangial cell proliferation and/or matrix accumulation characterizes many progressive renal diseases. PDGF-D was identified recently as a novel mediator of mesangial cell proliferation in vitro and in vivo. This study investigated the long-term consequences of PDGF-D inhibition in vivo. Rats with progressive mesangioproliferative glomerulonephritis (uninephrectomy plus anti-Thy-1.1 antibody) received the PDGF-D-neutralizing, fully human mAb CR002 on days 3, 10, and 17 after disease induction. Glomerular mesangioproliferative changes on day 10 were significantly reduced by anti-PDGF-D treatment as compared with control antibody. Eight weeks after disease induction, anti-PDGF-D therapy significantly ameliorated focal segmental glomerulosclerosis, podocyte damage (de novo desmin expression), tubulointerstitial damage, and fibrosis as well as the accumulation of renal interstitial matrix including type III collagen and fibronectin. Treatment with anti-PDGF-D also reduced the cortical infiltration of monocytes/macrophages on day 56, possibly related to lower renal cortical complement activation (C5b-9 deposition) and/or reduced epithelial-to-mesenchymal transition (preserved cortical expression of E-cadherin and reduced expression of vimentin and alpha-smooth muscle actin). In conclusion, these data provide evidence for a causal role of PDGF-D in the pathogenesis of renal scarring and point to a new therapeutic approach to progressive mesangioproliferative renal disease.
Ostendorf
Tammo
T
Division of Nephrology, University Hospital Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany. tostendorf@ukaachen.de
Rong
Song
S
Boor
Peter
P
Wiedemann
Stefanie
S
Kunter
Uta
U
Haubold
Ulrike
U
van Roeyen
Claudia R C
CR
Eitner
Frank
F
Kawachi
Hiroshi
H
Starling
Gary
G
Alvarez
Enrique
E
Smithson
Glennda
G
Floege
Jürgen
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D001483:Base Sequence; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D003167:Complement Activation; D018076:DNA, Complementary / Q000235:genetics; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005920:Glomerular Mesangium / Q000473:pathology; D015432:Glomerulonephritis, Membranoproliferative / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D008222:Lymphokines / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology; D008297:Male; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
D000911:Antibodies, Monoclonal; D018076:DNA, Complementary; D005353:Fibronectins; D008222:Lymphokines; C498952:Pdgfd protein, rat; D010982:Platelet-Derived Growth Factor; D003094:Collagen