Platelet-derived growth factor (PDGF) has been implicated in several nonmalignant pathophysiological processes, including proliferative diseases of the kidney. Glomerular mesangial cells secrete a PDGF-like factor and express the PDGF A-chain and c-sis (or B-chain) mRNAs. We report here that both mRNAs are induced by serum and this effect can be mimicked by recombinant PDGF, which also markedly stimulates DNA synthesis. Other growth factors, such as epidermal growth factor (EGF), transforming growth factor type alpha, basic fibroblast growth factor (bFGF), and tumor necrosis factor type alpha (TNF-alpha) also are mitogenic for human mesangial cells and induce expression of the PDGF mRNAs. EGF, TNF-alpha, and bFGF also stimulate these cells to secrete a PDGF-like factor. Furthermore, anti-PDGF antibody partially abrogates the mitogenic effect of EGF, suggesting that mitogen-stimulated PDGF synthesis in mesangial cells is at least partly responsible for cell growth induced by other growth factors. In contrast to these results, transforming growth factor type beta (TGF-beta), while inducing both mRNAs, is not mitogenic, indicating that its effect on message levels can be dissociated from DNA synthesis. These data suggest that several peptide growth factors regulate the growth of mesangial cells and that PDGF may be an effector molecule that plays a role in the mitogenic response to many of these growth stimuli.

Endothelin, a 17-DKa peptide originally described as a potent vasoconstrictor, also stimulates the release of important regulators of glomerular hemodynamics such as atrial natriuretic factor and renin. In the present study we investigated the role of endothelin in the release of another potent vasoconstrictor and mitogen of human mesangial cells, the platelet-derived growth factor. Endothelin stimulated PDGF release at 12 hours and the effect was sustained for 36 hours. This effect was associated with the enhanced induction of mRNAs encoding PDGF A- and B-chain. Endothelin also induced mitogenesis in human mesangial cells which was accompanied by activation of phospholipase C with increased inositol phosphate turnover. These data suggest a mechanism by which endothelin may regulate mesangial cell function in disease states.

Platelet-derived growth factor (PDGF) occurs as homodimers or heterodimers of related polypeptide chains PDGF-BB, -AA, and -AB. There are two receptors that bind PDGF, termed alpha and beta. The beta receptor recognizes PDGF B chain and is dimerized in response to PDGF BB. The alpha receptor recognizes PDGF B as well as A chains and can be dimerized by the three dimeric forms of PDGF AA, AB, and BB. To characterize PDGF receptor signaling mechanisms and biologic activities in human mesangial cells (MC), we explored the effects of the three PDGF isoforms on DNA synthesis, phospholipase C activation, and PDGF protooncogene induction. PDGF-BB homodimer and AB heterodimer induced a marked increase in DNA synthesis, activation of phospholipase C, and autoinduction of PDGF A and B chain mRNAs, whereas PDGF-AA homodimer was without effect. The lack of response to PDGF AA could be accounted for by down-regulation of the PDGF-alpha receptor since preincubation of MC with suramin restored PDGF AA-induced DNA synthesis. Ligand binding studies demonstrate specific binding of labeled PDGF BB and AB and to a lower extent PDGF AA isoforms to mesangial cells. These results are consistent with predominant expression of PDGF beta receptor in MC, which is linked to phospholipase-C activation. The potent biologic effects of PDGF-AB heterodimer in cells that express very few alpha receptors and do not respond to PDGF AA are somewhat inconsistent with the currently accepted model of PDGF receptor interaction and suggest the presence of additional mechanisms for PDGF isoform binding and activation.

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