PDGF-D inhibition by CR002 ameliorates tubulointerstitial fibrosis following experimental glomerulonephritis.
BACKGROUND
Arresting or regressing kidney scarring is of major clinical relevance. Platelet-derived growth factor D (PDGF-D) is widely expressed in fibrotic kidneys. Administration of the PDGF-D neutralizing fully human monoclonal antibody CR002 in the acute phase of progressive anti-Thy 1.1 glomerulonephritis reduced glomerular and secondary tubulointerstitial damage.


METHODS
Using this model, we now assessed the effects of CR002 (n=15) vs irrelevant control IgG (n=17) administered on days 17, 28 and 35 after disease induction, i.e. after acute glomerular damage had subsided.


RESULTS
In vitro, CR002 inhibited the PDGF-D- but not the PDGF-B-induced proliferation of rat renal fibroblasts. Following the first CR002 injection on day 17, exposure to therapeutic levels was maintained until day 49. Proteinuria in the CR002-treated group was transiently reduced between days 49 and 77 (-19 to -23% in comparison with the controls; P<0.05). On day 100, CR002 treatment reduced the number of rats that had doubled their serum creatinine (CR002: 40 vs controls: 71%; P<0.05). Compared with controls, the CR002 animals, on day 100, significantly lowered glomerular expression of vimentin and collagens as well as tubulointerstitial damage scores, interstitial fibrosis, vimentin and cortical PDGF-D mRNA levels.


CONCLUSIONS
PDGF-D antagonism, even after the phase of acute glomerular damage, exerts beneficial effects on the course of tubulointerstitial damage, i.e. the final common pathway of most renal diseases.
Boor
Peter
P
Division of Nephrology, University Hospital Aachen, Pauwelsstr. 30, D-52074 Aachen, Germany. boor@email.cz
Konieczny
Andrzej
A
Villa
Luigi
L
Kunter
Uta
U
van Roeyen
Claudia R C
CR
LaRochelle
William J
WJ
Smithson
Glennda
G
Arrol
Sharon
S
Ostendorf
Tammo
T
Floege
Jürgen
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D005355:Fibrosis / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D005921:Glomerulonephritis / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology*; D008222:Lymphokines / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000494:pharmacology; D008297:Male; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000494:pharmacology; D011507:Proteinuria / Q000503:physiopathology / Q000517:prevention & control; D051381:Rats; D017208:Rats, Wistar; D051437:Renal Insufficiency / Q000503:physiopathology / Q000517:prevention & control; D014746:Vimentin / Q000378:metabolism
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D008222:Lymphokines; C498952:Pdgfd protein, rat; D010982:Platelet-Derived Growth Factor; D014746:Vimentin