Biological responses to PDGF-AA versus PDGF-CC in renal fibroblasts.

Abstract

BACKGROUND:

Platelet-derived growth factors (PDGF)-AA and -CC mediate renal fibroblast proliferation and/or renal fibrosis. Whereas PDGF-CC binds to both the PDGF receptors (PDGFRs)-αα- and -αβ, PDGF-AA binds more selectively to the αα-receptor, suggesting potential differences in the biological activities.

METHODS:

We compared signal transduction, gene expression as well as changes in the proteome induced by PDGF-AA and -CC in rat renal fibroblasts, which express both PDGFR subunits. The growth factor concentrations used were chosen based on their equipotency in inducing rat renal fibroblast proliferation.

RESULTS:

Both PDGF-AA and PDGF-CC induced phosphorylation and activation of extracellular signal-regulated kinase 1 (ERK1) and ERK2. Renal fibroblast proliferation induced by either PDGF-AA or -CC could be blocked by signal transduction inhibitors of the mitogen-activated protein kinase (MAPK)-, Janus-kinase (JAK)/signal transducers and activators of transcription (STAT) and phosphatidyl-inositol-3-kinase (PI3K) pathway, pointing to the involvement of all the three pathways. However, quantitative differences between both the stimulations were minor. Additive or synergistic effects by stimulating simultaneously with PDGF-AA and -CC were not observed. Using a proteomic approach we found eleven differentially expressed proteins, which were quantitatively altered after treatment with either PDGF-AA or PDGF-CC. The regulation of calreticulin and inorganic pyrophosphatase 1 could be verified by western blotting.

CONCLUSIONS:

PDGF-AA and -CC exhibit almost identical biological effects on signal transduction and proteome in cultured renal fibroblasts, suggesting that the ligands exert their activity essentially through the commonly bound PDGFR-αα. Nonetheless, two differentially expressed proteins were identified which might be involved in the development of renal failure.

• Authors: Claudia Seikrit, Corinna Henkel, Claudia R C van Roeyen, Dirk Bokemeyer, Frank Eitner, Ina V Martin, Peter Boor, Ruth Knüchel, Helmut E Meyer, Gerhard Müller-Newen, Ulf Eriksson, Jürgen Floege, Tammo Ostendorf
• Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant) Vol. 28 Issue 4 Pg. 889-900 (Apr 2013) ISSN: 1460-2385 [Electronic] England
• PMID: 23229927 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lymphokines
• Platelet-Derived Growth Factor
• RNA, Messenger
• platelet-derived growth factor A
• platelet-derived growth factor C
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Animals
• Blotting, Western
• Cell Proliferation
• Cells, Cultured
• Electrophoresis, Gel, Two-Dimensional
• Electrophoretic Mobility Shift Assay
• Fibroblasts (cytology, metabolism)
• Kidney (cytology, metabolism)
• Lymphokines (genetics, metabolism)
• Mitogen-Activated Protein Kinase 1 (genetics, metabolism)
• Mitogen-Activated Protein Kinase 3 (genetics, metabolism)
• Phosphorylation
• Platelet-Derived Growth Factor (genetics, metabolism)
• Proteomics
• RNA, Messenger (genetics)
• Rats
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction
• Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization