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The Effects of Platelet-Derived Growth Factor Antagonism in Experimental Glomerulonephritis Are Independent of the Transforming Growth Factor–ß System

Tammo Ostendorf^*, Uta Kunter^*, Claudia van Roeyen^*, Steven Dooley, Nebojsa Janjic, Judy Ruckman, Frank Eitner and Jürgen Floege^*

*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.

Correspondence to Dr. Jürgen Floege, University of Aachen, Medizinische Klinik II, Klinikum der RWTH, Pauwelsstrasse 30, 52074 Aachen, Germany. Phone: 49-241-8089530; Fax: 49-241-8888446; E-mail: juergen.floege{at}post.rwth-aachen.de

ABSTRACT. Platelet-derived growth factor B-chain (PDGF-B)– and transforming growth factor beta (TGF-ß)–mediated accumulation of extracellular matrix proteins contributes to many progressive renal diseases. In vivo, specific antagonism of either PDGF-B or TGF-ß 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-ß 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-ß mRNA, TGF-ß protein, or the expression of TGF-ß receptor type I and II mRNA. By immunohistology, it was possible to detect overexpression of the cytoplasmic TGF-ß 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-ß in mesangioproliferative glomerulonephritides.

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