Biological responses to PDGF-BB versus PDGF-DD in human mesangial cells.
Platelet-derived growth factor (PDGF)-BB and PDGF-DD mediate mesangial cell proliferation in vitro and in vivo. While PDGF-BB is a ligand for the PDGF alpha- and beta-receptor chains, PDGF-DD binds more selectively to the beta-chain, suggesting potential differences in the biological activities. Signal transduction and regulation of gene expression induced by PDGF-BB and -DD were compared in primary human mesangial cells (HMCs), which expressed PDGF alpha- and beta-receptor subunits. The growth factor concentrations used were chosen based on their equipotency in inducing HMCs proliferation and binding to the betabeta-receptor. Both growth factors, albeit at different concentrations induced phosphorylation and activation of extracellular signal-regulated kinase 1 (ERK1) and ERK2. In addition, PDGFs led to the phosphorylation and activation of signal transducers and activators of transcription 1 (STAT1) and STAT3. HMCs proliferation induced by either PDGF-BB or -DD could be blocked by signal transduction inhibitors of the mitogen-activated protein kinase-, Janus kinase (JAK)/STAT-, or phosphatidyl-inositol 3-kinase pathways. Using a gene chip array and subsequent verification by real-time reverse transcriptase (RT)-polymerase chain reaction, we found that in HMC genes for matrix metalloproteinase 13 (MMP-13) and MMP-14 and, to a low extent, cytochrome B5 and cathepsin L were exclusively regulated by PDGF-BB, whereas no exclusive gene regulation was detected by PDGF-DD. However, at the protein level, both MMP-13 and -14 were equally induced by PDGF-BB and -DD. PDGF-BB and -DD effect similar biological responses in HMCs albeit at different potencies. Rare apparently differential gene regulation did not result in different protein expression, suggesting that in HMCs both PDGFs exert their biological activity almost exclusively via the PDGF beta-receptor.
Division of Nephrology, RWTH Aachen University, Aachen, Germany.
C R C
CR
van Roeyen
T
T
Ostendorf
B
B
Denecke
D
D
Bokemeyer
I
I
Behrmann
F
F
Strutz
H S
HS
Lichenstein
W J
WJ
LaRochelle
C E
CE
Pena
A
A
Chaudhuri
J
J
Floege
D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000378:metabolism; D000077214:Becaplermin; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D017364:Collagenases / Q000378:metabolism; D003720:Densitometry; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases / Q000378:metabolism; D053504:Matrix Metalloproteinases, Membrane-Associated; D050527:Mesangial Cells / Q000187:drug effects*; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000494:pharmacology*; D040081:Protein Array Analysis; D020033:Protein Isoforms / Q000235:genetics / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012015:Reference Standards; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
D043925:Angiogenesis Inducing Agents; D000911:Antibodies, Monoclonal; D010982:Platelet-Derived Growth Factor; D020033:Protein Isoforms; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D011994:Recombinant Proteins; D000077214:Becaplermin; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated