Inhibition of mesangial cell proliferation by platelet factor 4.

Abstract

Platelet factor 4(PF4), an abundant platelet secretory product, is a strong candidate for modulating glomerular pathology. Because PF4 might be released from platelets and influence intrinsic cell growth during glomerular injury, the effect of PF4 on fetal calf serum- and platelet-derived growth factor (PDGF)-induced mesangial cell mitogenesis was examined. Mitogenesis was measured as the amount of 3H-thymidine incorporated into acid-precipitable material as well as by autoradiography. The effect of PF4 on mesangial cell expression of mRNA for PDGF A chain and transforming growth factor-beta (TGF-beta 1) was also examined. Fetal calf serum (10%)- and PDGF (10 ng/mL)-stimulated increases in mesangial cell 3H-thymidine incorporation were inhibited by incremental concentrations of PF4 (1 to 25 micrograms/mL) showing a maximum reduction of approximately 80% at 25 micrograms/mL of PF4. PF4 was effective when added 24 h before and 1, 4, and 8 h, but not 16 h after the addition of PDGF, indicating that inhibition occurred at delayed events in cell-cycle regulation. PF4 inhibited PDGF-induced increments in mRNA encoding PDGF A chain and TGF-beta 1. Also, PF4 did not interfere with PDGF receptor binding. The results of this study show that PF4 is a negative regulator of mesangial cell proliferation and suggest an interference in cell growth by pathways associated with modulation of the autocrine growth factors PDGF and TGF-beta 1.