Heparin attenuates the effect of mitogenic vasoconstrictors on mesangial cell proliferation and handling of immunoglobulin G complexes.
Angiotensin II (ANG II) and endothelin-1 (ET-1) may both play significant roles in causing mesangial expansion and glomerulosclerosis after renal injury by enhancing mesangial cell (MC) proliferation and by increasing MC uptake of macromolecules. Heparin has been demonstrated to significantly ameliorate the development of glomerulosclerosis in animal models of progressive renal injury, although the mechanism is unknown. We undertook the present study to examine in an in vitro system the mechanism by which heparin might modulate the effects of ANG II and ET-1 on MC proliferation and MC uptake of immunoglobulin G (IgG) complexes. Heparin was found to suppress MC uptake of IgG complexes in a concentration-related manner. Whereas ANG II significantly enhanced (P < .01) uptake of IgG complexes, this increase was significantly antagonized (P < .01) by coincubation of MC with heparin at therapeutic concentration (1 U/ml). ET-1 also was found to significantly increase MC uptake of IgG complexes (P < .02), and this increase also was significantly antagonized by coincubation with heparin (P < .02). Heparin was found to inhibit surface binding of IgG to MC in a concentration-related manner (55% reduction at 1 U/ml). MC [3H]thymidine incorporation was significantly enhanced by both ANG II (P < .01) and ET-1 (P < .001) and these mitogenic effects were significantly attenuated by coincubation of cells with heparin (P < .01 and P < .001, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Mattana
J
J
Department of Medicine, Long Island Jewish Medical Center, New Hyde Park, New York, USA.
Singhal
P C
PC
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects*; D006493:Heparin / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D016232:Endothelins; D007074:Immunoglobulin G; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D009569:Nitric Oxide; D006493:Heparin; D001120:Arginine; D019331:NG-Nitroarginine Methyl Ester