Specific antagonism of PDGF prevents renal scarring in experimental glomerulonephritis.
Glomerular mesangial cell proliferation and/or mesangial matrix accumulation characterizes many progressive renal diseases. Rats with progressive mesangioproliferative glomerulonephritis were treated from day 3 to day 7 after disease induction with a high-affinity oligonucleotide aptamer antagonist against platelet-derived growth factor-B chain (PDGF-B). In comparison with nephritic rats that received vehicle or a scrambled aptamer, treatment with the PDGF-B aptamer led to a significant reduction of mesangioproliferative changes, glomerular hypertrophy, podocyte damage, and glomerular macrophage influx on day 8. Both nephritic control groups subsequently developed progressive proteinuria and decreased renal function. On day 100, glomerulosclerosis, tubulointerstitial damage, glomerular and interstitial accumulation of types III and IV collagen, and overexpression of transforming growth factor-beta were widespread. All of these chronic changes were prevented in rats that received the PDGF-B aptamer, and their functional and morphologic parameters on day 100 were largely indistinguishable from non-nephritic rats. These data provide the first evidence for a causal role of PDGF in the pathogenesis of renal scarring and point to a new, highly effective therapeutic approach to progressive, in particular mesangioproliferative, renal disease.
Ostendorf
Tammo
T
Medizinische Klinik II, University of Aachen, Aachen, Germany.
Kunter
Uta
U
Medizinische Klinik II, University of Aachen, Aachen, Germany.
Gröne
Hermann Joseph
HJ
Department of Pathology, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Bahlmann
Ferdinand
F
Division of Nephrology, Medizinische Hochschule, Hannover, Germany.
Kawachi
Hiroshi
H
Department of Cell Biology, Institute of Nephrology, Niigata School of Medicine, Niigata, Japan.
Shimizu
Fujio
F
Department of Cell Biology, Institute of Nephrology, Niigata School of Medicine, Niigata, Japan.
Koch
Karl Martin
KM
Division of Nephrology, Medizinische Hochschule, Hannover, Germany.
Janjic
Nebojsa
N
NeXstar Pharmaceuticals, Boulder, Colorado.
Floege
Jürgen
J
Medizinische Klinik II, University of Aachen, Aachen, Germany.
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002921:Cicatrix / Q000517:prevention & control; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D015432:Glomerulonephritis, Membranoproliferative / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D008854:Microscopy, Electron; D009000:Monocytes / Q000187:drug effects / Q000473:pathology; D011507:Proteinuria / Q000517:prevention & control; D020574:Proto-Oncogene Proteins c-sis / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000378:metabolism
D020574:Proto-Oncogene Proteins c-sis; D016212:Transforming Growth Factor beta; D003094:Collagen