Angiotensin II and basic fibroblast growth factor mitogenic pathways in human fetal mesangial cells

Angiotensin II (Ang II) and basic fibroblast growth factor (bFGF/FGF-2) pla y relevant roles in renal development. Since the signaling pathways modulat ing the mitogenic effects of Ang LI and bFGF in human fetal mesangial cells (HFMc) are not clearly defined, we carried out experiments to determine wh ether they would exert their mitogenic effects by modulating the activity o f the mitogen-activated protein kinases (MAPK) [extracellular signal-regula ted kinase-2 (ERK-2)] and cAMP signaling pathways. In confluent HFMc, bFGF (20 ng/mL) induced a significant 4-fold increase in ERK-2 activity and [H-3 ]-thymidine incorporation (6-fold). In contrast, under similar tissue cultu re conditions, Ang II (10(-6) M) induced a more modest increase in ERK-2 ac tivity (2-fold) and [H-3]-thymidine incorporation (35 +/- 4%). The mitogen- activated protein kinase kinase-l (MEK-1) inhibitor PD098059 (25 mu M) almo st completely abolished the bFGF-induced proliferation in HFMc but did not significantly affect Ang II proliferative effects, In the presence of the c AMP elevating agent isoproterenol, Ang II and bFGF induced opposite changes in cAMP accumulation and cell growth. Isoproterenol inhibited the basal an d bFGF-induced proliferation of HFMc through a MEK-1/2-independent pathway that included the accumulation of cAMP, In contrast, isoproterenol increase d Ang II mitogenic effects in correlation with a reduction in cAMP accumula tion. We conclude that Ang II and bFGF modulate the proliferation of HFMc t hrough the stimulation of different MEK-1/2-dependent and independent signa ling pathways. Activation of MEK-1/2 is required but not sufficient fur mit ogenesis in HFMc. The accumulation of cAMP in HFMc counteracts the mitogeni c effects of bFGF by a MEK-1/1-independent pathway.