The effects of platelet-derived growth factor antagonism in experimental glomerulonephritis are independent of the transforming growth factor-beta system.
Platelet-derived growth factor B-chain (PDGF-B)- and transforming growth factor beta (TGF-beta)-mediated accumulation of extracellular matrix proteins contributes to many progressive renal diseases. In vivo, specific antagonism of either PDGF-B or TGF-beta in experimental mesangioproliferative glomerulonephritis resulted in an almost complete inhibition of matrix protein accumulation, which suggests an interaction between signaling pathways of these two growth factors. Because nothing is known on the nature of this possible interaction, PDGF-B was antagonized in the rat anti-Thy 1.1 model of glomerulonephritis by use of specific aptamers and its effects on the TGF-beta system were investigated. Antagonism of PDGF-B led to a significant reduction of glomerular matrix accumulation compared with scrambled aptamer-treated nephritic controls. PDGF-B antagonism had no effect on the overexpression of glomerular TGF-beta mRNA, TGF-beta protein, or the expression of TGF-beta receptor type I and II mRNA. By immunohistology, it was possible to detect overexpression of the cytoplasmic TGF-beta signaling molecules Smad2 (agonistic) and Smad7 (antagonistic) in glomeruli of nephritic control rats which peaked on day 7 after disease induction, i.e., the peak of mesangial cell proliferation in this model. However, immunohistology and Western blot analysis again revealed no difference in the glomerular expression of both Smad proteins between PDGF-B antagonized and nonantagonized nephritic animals. In addition, no difference in the glomerular expression of phosphorylated Smad2 (P-Smad2) was detected between the differently treated nephritic groups. These observations suggest that the effects of PDGF-B antagonism are independent of TGF-beta in mesangioproliferative glomerulonephritides.
Ostendorf
Tammo
T
*Division of Nephrology and Immunology and Institute of Clinical Chemistry and Pathobiochemistry, University of Aachen, Aachen, Germany; Replidyne, Inc., Denver, Colorado; and Gilead Sciences, Inc., Boulder, Colorado.
Kunter
Uta
U
*Division of Nephrology and Immunology and Institute of Clinical Chemistry and Pathobiochemistry, University of Aachen, Aachen, Germany; Replidyne, Inc., Denver, Colorado; and Gilead Sciences, Inc., Boulder, Colorado.
van Roeyen
Claudia
C
*Division of Nephrology and Immunology and Institute of Clinical Chemistry and Pathobiochemistry, University of Aachen, Aachen, Germany; Replidyne, Inc., Denver, Colorado; and Gilead Sciences, Inc., Boulder, Colorado.
Dooley
Steven
S
*Division of Nephrology and Immunology and Institute of Clinical Chemistry and Pathobiochemistry, University of Aachen, Aachen, Germany; Replidyne, Inc., Denver, Colorado; and Gilead Sciences, Inc., Boulder, Colorado.
Janjic
Nebojsa
N
*Division of Nephrology and Immunology and Institute of Clinical Chemistry and Pathobiochemistry, University of Aachen, Aachen, Germany; Replidyne, Inc., Denver, Colorado; and Gilead Sciences, Inc., Boulder, Colorado.
Ruckman
Judy
J
*Division of Nephrology and Immunology and Institute of Clinical Chemistry and Pathobiochemistry, University of Aachen, Aachen, Germany; Replidyne, Inc., Denver, Colorado; and Gilead Sciences, Inc., Boulder, Colorado.
Eitner
Frank
F
Floege
Jürgen
J
*Division of Nephrology and Immunology and Institute of Clinical Chemistry and Pathobiochemistry, University of Aachen, Aachen, Germany; Replidyne, Inc., Denver, Colorado; and Gilead Sciences, Inc., Boulder, Colorado.
D000818:Animals; D002455:Cell Division / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005921:Glomerulonephritis / Q000276:immunology / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000166:cytology / Q000378:metabolism; D008297:Male; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D051899:Smad2 Protein; D051906:Smad7 Protein; D018800:Thy-1 Antigens / Q000276:immunology; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology*; D053773:Transforming Growth Factor beta1
D004268:DNA-Binding Proteins; D016326:Extracellular Matrix Proteins; D010982:Platelet-Derived Growth Factor; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D051906:Smad7 Protein; C497808:Smad7 protein, rat; C508962:Tgfb1 protein, rat; D018800:Thy-1 Antigens; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1