Journal
KIDNEY INTERNATIONAL
Volume 75, Issue 11, Pages 1173-1183Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/ki.2009.44
Keywords
glomerular disease; mesangial cell; receptor tyrosine kinase; signal transduction; transactivation
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Funding
- High-Tech Research Center Project
- Vehicle Racing Commemorative Foundation
- Sankyo Foundation of Life Science
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Although it is well known that platelet-derived growth factor (PDGF) causes mesangial cell proliferation (presumably contributing to progression of glomerular disease), targeted inhibition of the PDGF receptor system has shown only limited efficacy against glomerular diseases. To examine whether this discrepancy is due to the involvement of other pathways, we used phosphorylated receptor tyrosine kinase arrays and found that RON (recepteur d'origine nantais) was phosphorylated while the PDGF receptor was dephosphorylated (thus inactive) in human mesangial cells (HMCs) at the time of cell cycle entry. Further, RON remained active during steady-state growth. Activation of RON was independent of its canonical ligand, macrophage-stimulating protein, but was mediated by transactivation from the PDGF-engaged PDGF receptor. Following stimulation with PDGF we found that the two receptors physically interacted. Knockdown of RON by siRNA increased the number of apoptotic cells without affecting the rate of DNA synthesis, suggesting that RON has anti-apoptotic functions. Immunohistochemical analysis found phosphorylated RON in glomerular lesions of patients with IgA nephropathy but not those with minimal change nephrotic syndrome, a disease not associated with mesangial proliferation. These results suggest that RON is involved in mesangial cell proliferation under both physiological and pathological conditions, and may be a relevant target for therapeutic intervention. Kidney International (2009) 75, 1173-1183; doi:10.1038/ki.2009.44; published online 25 February 2009
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