Basic Fibroblast Growth Factor Stimulates Glomerular Mesangial Cell Proliferation Through a Protein Kinase C-Independent Pathway

Abstract

Basic Fibroblast Growth Factor (bFGF) is shown to be a potent mitogen for cultured glomerular mesangial cells. bFGF induces an increase in cell number and stimulates DNA synthesis measured by [3H]thymidine incorporation in normal as well as in protein kinase C-depleted cells. The ED50 observed in both cases are nearly identical (approximately 0.04 nM) and maximal responses are obtained at 1 nM. Staurosporine, a potent protein kinase C inhibitor, does not prevent bFGF from inducing mitogenesis. On the contrary, the tumour promoting phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) and the bradykinin derivative Des-Arg9bradykinin that we have previously shown as mitogens for mesangial cells, fail to trigger DNA synthesis or cell proliferation upon staurosporine treatment or in protein kinase C-depleted cells. bFGF is unable to induce the association of the enzyme to membranes, the so-called translocation process, although the growth factor induces a slight production of diacylglycerol. Using a highly resolutive two-dimensional electrophoresis, we show that bFGF, in contrast to TPA, is unable to stimulate the phosphorylation of a Mr 80,000/pI 4.5 protein, a major and specific protein kinase C substrate. By contrast, bFGF stimulates the phosphorylation of a Mr 28,000/pI 5.7-5.9 protein in normal as well as in protein kinase C-depleted cells while TPA induces this protein phosphorylation only in normal cells. Our results suggest that bFGF exerts its proliferative action on mesangial cells through a protein kinase C-independent pathway and that the growth factor does not activate anyway the enzyme in this cell type.

Basic fibroblast growth factor selectively regulates ornithine decarboxylase gene expression in malignant H-ras transformed cells

“…This observation, coupled with the inability of PKC inhibitors to abrogate the bFGF-mediated elevation in ODC mRNA expression in malignant cells, suggests that the bFGF-mediated alterations in ODC mRNA expression in highly malignant H-ras transformed fibrosarcoma cells occurs through a protein kinase C-independent pathway. These observations are in keeping with several studies which suggest that the mitogeniclproliferative effects of FGFs may not be mediated by protein kinase C activation [Chambard et al, 1987;Issandau and Darbon, 1991;Kaibuchi et al, 1986;Magnaldo et al, 19861. The exact nature of the signal transduction pathway involved in these malignant H-rus transformed cells remains to be further elucidated.…”

The Accumulation of Heparan Sulfate S-Domains in Kidney Transthyretin Deposits Accelerates Fibril Formation and Promotes Cytotoxicity

“…Optimal activities of FGF2 require glypicans, 72 including GPC5. 73 Although FGF2 stimulated proliferation of glomerular mesangial cells, endothelial cells, and podocytes, 71,74,75 an excess amount of FGF2 was harmful to glomeruli and induced proteinuria. 76,77 Podocyte-specific knockdown of GPC5 has also reduced FGF2-induced podocyte injury and proteinuria by inhibiting FGF2 binding to cells.…”

c-Jun NH2-terminal kinase mediation of angiotensin II-induced proliferation of human mesangial cells

“…We found that SP-600125 at a dose of up to 20 M had no significant effect on LDH release, thus ruling out the cytotoxicities of the compound under current experimental conditions. It is well recognized that MC proliferation can be stimulated by activation of tyrosine kinase receptors for epidermal growth factor (EGF) (7,36), platelet derived growth factor (PDGF) (1,7), and bFGF (8,17), and of G protein-coupled receptors for ANG II (2, 16) and endothelin-1 (33,34). The signaling transductions elicited by activation of tyrosine kinase receptors and G protein-coupled receptors converge at Erk1/2.…”