TRPC6 channel activation promotes neonatal glomerular mesangial cell apoptosis via calcineurin/NFAT and FasL/Fas signaling pathways

Abstract

Glomerular mesangial cell (GMC) proliferation and death are involved in the pathogenesis of glomerular disorders. The mechanisms that control GMC survival are poorly understood, but may include signal transduction pathways that are modulated by changes in intracellular Ca2+ ([Ca2+]i) concentration. In this study, we investigated whether activation of the canonical transient receptor potential (TRPC) 6 channels and successive [Ca2+]i elevation alter neonatal GMC survival. Hyperforin (HF)-induced TRPC6 channel activation increased [Ca2+]i concentration, inhibited proliferation, and triggered apoptotic cell death in primary neonatal pig GMCs. HF-induced neonatal GMC apoptosis was not associated with oxidative stress. However, HF-induced TRPC6 channel activation stimulated nuclear translocation of the nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1). HF also increased cell death surface receptor Fas ligand (FasL) level and caspase-8 activity in the cells; effects mitigated by [Ca2+]i chelator BAPTA, calcineurin/NFAT inhibitor VIVIT, and TRPC6 channel knockdown. Accordingly, HF-induced neonatal GMC apoptosis was attenuated by BAPTA, VIVIT, Fas blocking antibody, and a caspase-3/7 inhibitor. These findings suggest that TRPC6 channel-dependent [Ca2+]i elevation and the ensuing induction of the calcineurin/NFAT, FasL/Fas, and caspase signaling cascades promote neonatal pig GMC apoptosis.

γ‐secretase inhibitor DAPT mitigates cisplatin‐induced acute kidney injury by suppressing Notch1 signaling

“…Apoptosis of HK‐2 cells was examined in real time using the CellPlayer caspase‐3/7 reagent, and the IncuCyte ZOOM live content microscopy system (Essen BioScience, Ann Arbor, MI, USA) as we have previously described . Cytotoxicity was also determined using the LDH colorimetric assay kit (Life Technologies).…”

Rosiglitazone Inhibits Angiotensin II-Induced Proliferation of Glomerular Mesangial Cells via the Gαq/Plcβ4/TRPC Signaling Pathway

“…Continuous Ca 2+ entries through the TRPC1 and 6 channels may activate the calcineurin/NFAT (nuclear factor of activated T cells) signaling pathway and then promote proliferation of T lymphocytes [41]. Additionally, translocation of NFATc1 via the TRPC6 channel was also found to be essential in neonatal pig glomerular mesangial cells, although activation of TRPC6 was shown to inhibit cell proliferation and promote cell apoptosis in neonatal pig glomerular mesangial cells [42]. We believe that different animal species and cell conditions may have different profiles of TRPC isoforms, which may result in substantially different consequences.…”

Ion channels as therapeutic antibody targets

“…161 This in turn promotes glomerular mesangial cell apoptosis via calcineurin/NFAT and FasL/Fas signaling pathways. 295 Additionally, mice with podocyte-specific overexpression of TrpC6 recapitulate many of the pathological features of FSGS. 296 Despite the clear association of TrpC6 with FSGS, there are currently no clinical trials of therapeutics targeting TrpC6 for any condition.…”