Interleukin 1 beta-induced calcium signaling via TRPA1 channels promotes mitogen-activated protein kinase-dependent mesangial cell proliferation.

Glomerular mesangial cell (GMC)-derived pleiotropic cytokine, interleukin-1 (IL-1), contributes to hypercellularity in human and experimental proliferative glomerulonephritis. IL-1 promotes mesangial proliferation and may stimulate extracellular matrix accumulation, mechanisms of which are unclear. The present study shows that the beta isoform of IL-1 (IL-1β) is a potent inducer of IL-1 type I receptor-dependent Ca2+ entry in mouse GMCs. We also demonstrate that the transient receptor potential ankyrin 1 (TRPA1) is an intracellular store-independent diacylglycerol-sensitive Ca2+ channel in the cells. IL-1β-induced Ca2+ and Ba2+ influxes in the cells were negated by pharmacological inhibition and siRNA-mediated knockdown of TRPA1 channels. IL-1β did not stimulate fibronectin production in cultured mouse GMCs and glomerular explants but promoted Ca2+ -dependent cell proliferation. IL-1β also stimulated TRPA1-dependent ERK mitogen-activated protein kinase (MAPK) phosphorylation in the cells. Concomitantly, IL-1β-induced GMC proliferation was attenuated by TRPA1 and RAF1/ MEK/ERK inhibitors. These findings suggest that IL-1β-induced Ca2+ entry via TRPA1 channels engenders MAPK-dependent mesangial cell proliferation. Hence, TRPA1-mediated Ca2+ signaling could be of pathological significance in proliferative glomerulonephritis.