Abstract
Angiotensin II (Ang II) and basic fibroblast growth factor (bFGF/FGF-2) play relevant roles in renal development. Since the signaling pathways modulating the mitogenic effects of Ang II and bFGF in human fetal mesangial cells (HFMc) are not clearly defined, we carried out experiments to determine whether they would exert their mitogenic effects by modulating the activity of the mitogen-activated protein kinases (MAPK) [extracellular signal-regulated 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 [3H]-thymidine incorporation (6-fold). In contrast, under similar tissue culture conditions, Ang II (10−6 M) induced a more modest increase in ERK-2 activity (2-fold) and [3H]-thymidine incorporation (35 ± 4%). The mitogen-activated protein kinase kinase-1 (MEK-1) inhibitor PD098059 (25 μM) almost completely abolished the bFGF-induced proliferation in HFMc but did not significantly affect Ang II proliferative effects. In the presence of the cAMP elevating agent isoproterenol, Ang II and bFGF induced opposite changes in cAMP accumulation and cell growth. Isoproterenol inhibited the basal and bFGF-induced proliferation of HFMc through a MEK-1/2–independent pathway that included the accumulation of cAMP. In contrast, isoproterenol increased Ang II mitogenic effects in correlation with a reduction in cAMP accumulation. We conclude that Ang II and bFGF modulate the proliferation of HFMc through the stimulation of different MEK-1/2–dependent and independent signaling pathways. Activation of MEK-1/2 is required but not sufficient for mitogenesis in HFMc. The accumulation of cAMP in HFMc counteracts the mitogenic effects of bFGF by a MEK-1/2–independent pathway.
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Abbreviations
- HFMc:
-
human fetal mesangial cells
- bFGF:
-
basic fibroblast growth factor
- Ang II:
-
angiotensin II
- MAPK:
-
mitogen-activated protein kinases
- ERK:
-
extracellular signal-regulated kinases
- MEK-1 and -2:
-
MAP kinase kinase 1 and 2
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Supported by USPHS awards R0–1DK 4919 and RO-1HL 55605, “FADI” from Buenos Aires, Argentina, and NIDDK training grant # DK49419-S1 (E.B.I.).
Presented in part at the American Pediatric Society–Society for Pediatric Research Annual Meeting, San Francisco, May 1–4, 1999.
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Izevbigie, E., Gutkind, J. & Ray, P. Angiotensin II and Basic Fibroblast Growth Factor Mitogenic Pathways in Human Fetal Mesangial Cells. Pediatr Res 47, 614–621 (2000). https://doi.org/10.1203/00006450-200005000-00010
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DOI: https://doi.org/10.1203/00006450-200005000-00010
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