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. [ABSTRACT FROM AUTHOR]