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 pathogenesis 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 polyaromatic "heparin mimicking" compound (RG-13577, polymer of 4-hydroxyphenoxy acetic acid, M(r) approximately 5800), previously reported to inhibit the proliferation of vascular smooth muscle cells, was applied. RG-13577 exhibits approximately 1% of the anticoagulant activity of heparin and is nontoxic in animal experiments. Proliferation of primary rat MC was almost completely inhibited in the presence of 10 to 25 micrograms/ml RG-13577, and 50% inhibition was obtained at 1 to 5 micrograms/ml RG-13577. The cells resumed their normal growth rate after removal of RG-13577 from the culture medium. Under the same conditions, heparin exerted only a small inhibitors effect. RG-13577 inhibited signaling (i.e., tyrosine phosphorylation) and MC proliferation induced by both basic fibroblast growth factor and platelet-derived growth factor. RG-13577 binds to a naturally produced extracellular matrix, and the bound molecule retained its antiproliferative effect toward MC. 14C-Labeled RG-13577 also binds to cultured MC in a specific and saturable manner. Binding of 14C-RG-13577 was reduced by 80 to 90% in the presence of excess unlabeled RG-13577, apolipoprotein E, or lactoferrin, but there was no effect with heparin. Furthermore, the antiproliferative effect of RG-13577 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, and possibly through binding to specific cell surface receptors, most likely the LDL receptor-related protein. RG-13577 and related polyanionic compounds may be applied to inhibit MC proliferation in glomerular diseases.
Katz
A
A
Department of Oncology, Hadassah-Hebrew University Hospital, Jerusalem, Israel.
Vlodavsky
I
I
Davies
M
M
Miao
H Q
HQ
Ben-Sasson
S A
SA
Darmon
D
D
Hurwitz
H
H
Borgel
H
H
Benezra
M
M
D000818:Animals; D001665:Binding Sites; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical; D005109:Extracellular Matrix / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000187:drug effects; D005920:Glomerular Mesangium / Q000166:cytology* / Q000187:drug effects*; D006493:Heparin / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008970:Molecular Weight; D010642:Phenoxyacetates / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011108:Polymers / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D012680:Sensitivity and Specificity; D014443:Tyrosine / Q000737:chemistry
D010642:Phenoxyacetates; D011108:Polymers; C090697:2-(4-hydroxyphenoxy)acetic acid-formaldehyde polymer; D014443:Tyrosine; D005346:Fibroblast Growth Factors; D006493:Heparin