ANTIPROLIFERATIVE ACTIVITY TO GLOMERULAR MESANGIAL CELLS AND RECEPTOR-BINDING OF A HEPARIN-MIMICKING POLYAROMATIC ANIONIC COMPOUND

Proliferation of mesangial cells (MC) is a key feature in the pathogen esis of numerous renal diseases involving the glomerulus. Heparin, one of several compounds capable of suppressing MC proliferation, did not prove beneficial in the treatment of human glomerular diseases. In a search for a superior antiproliferative agent, a synthetic polyaromati c ''heparin mimicking'' compound (RG-13577, polymer of 4-hydroxyphenox y acetic acid, M-r,approximately 5800), previously reported to inhibit the proliferation of vascular smooth muscle cells, was applied. RG-13 577 exhibits approximately 1% of the anticoagulant activity of heparin and is nontoxic in animal experiments. Proliferation of primary rat M C was almost completely inhibited in the presence of 10 to 25 mu g/ml RG-13577, and 50% inhibition was obtained at 1 to 5 mu g/ml RG-13577. The cells resumed their normal growth rate after removal of RG-13577 f rom the culture medium. Under the same conditions, heparin exerted onl y a small inhibitory effect. RG-13577 inhibited signaling (i.e., tyros ine phosphorylation) and MC proliferation induced by both basic fibrob last growth factor and platelet-derived growth factor. RG-13577 binds to a naturally produced extracellular matrix, and the bound molecule r etained its antiproliferative effect toward MC. C-14-Labeled RG-13577 also binds to cultured MC in a specific and saturable manner. Binding of C-14-RG-13577 was reduced by 80 to 90% in the presence of excess un labeled RG-13577, apolipoprotein E, or lactoferrin, but there was no e ffect with heparin. Furthermore, the antiproliferative effect of RG-13 577 was abolished in the presence of lactoferrin. It is proposed that compound RG-13577 inhibits MC proliferation through neutralization of growth-promoting factors, primarily heparin-binding growth factors, an d possibly through binding to specific cell surface receptors, most li kely the LDL receptor-related protein. RG-13577 and related polyanioni c compounds may be applied to inhibit MC proliferation in glomerular d iseases.