Bradykinin stimulates c-fos expression, AP-1-DNA binding activity and proliferation of rat glomerular mesangial cells

An important role for bradykinin (BK) in nephrogenesis has been suggested based on impairment of renal growth in developing rats treated with a kinin antagonist. However, direct effects of BK on renal cell mitogenesis have not been reported. In the present study, we examined the mitogenic effects of BK on cultured rat mesangial cells. Transcripts encoding BK-B2 receptors were detected in quiescent and proliferating mesangial cells by reverse transcription-coupled polymerase chain reaction. In quiescent mesangial cell cultures (0.5% FCS for 48 hr), BK (10(-9) to 10 (-7)M) caused a significant increase in DNA synthesis (3H-thymidine incorporation into DNA) and cell number. BK-induced DNA synthesis was preceded by activation of c-fos gene expression and both of these effects were inhibited by Hoe-140, a specific BK-B2 antagonist. Electrophoretic gel mobility shift assays revealed enhanced binding of AP-1 complexes to a consensus AP-1 DNA sequence in BK-stimulated cells. Gel supershift assays confirmed that the AP-1 complexes contained the fos protein. These data document a direct mitogenic effect of BK, acting on B2 receptors, on mesangial cells.