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Activation of TRPC6 channels contributes to (+)-conocarpan-induced apoptotic cell death in HK-2 cells
- Yang, Guoling, Ma, Hui, Wu, Yanliang, Zhou, Baoping, Zhang, Chunlei, Chai, Chengzhi, Cao, Zhengyu
- Food and chemical toxicology 2019 v.129 pp. 281-290
- apoptosis, calcium, electrophysiology, food plants, humans, inhibitory concentration 50, lignans, median effective concentration, nephrotoxicity, risk, therapeutics
- (+)-Conocarpan (CNCP), a neolignan frequently found in many medicinal and edible plants displays a broad spectrum of bioactivity. Here, we demonstrated that CNCP induced apoptotic cell death in human kidney-2 (HK-2) cells in a concentration-dependent manner (IC50 = 19.3 μM) and led to the sustained elevation of intracellular Ca2+ ([Ca2+]i). Lower extracellular Ca2+ concentrations from 2.3 mM to 0 mM significantly suppressed the CNCP-induced Ca2+ response by 69.1%. Moreover, the depletion of intracellular Ca2+ stores using thapsigargin normalized CNCP-induced Ca2+ release from intracellular Ca2+ stores, suggesting that the CNCP-induced Ca2+ response involved both extracellular Ca2+ influx and Ca2+ release from intracellular Ca2+ stores. SAR7334, a TRPC3/6/7 channel inhibitor, but neither Pyr3, a selective TRPC3 channel inhibitor, nor Pico145, a TRPC1/4/5 inhibitor, suppressed the CNCP-induced Ca2+ response by 57.2% and decreased CNCP-induced cell death by 53.4%, suggesting a critical role for TRPC6 channels in CNCP-induced Ca2+ influx and apoptotic cell death. Further electrophysiological recording demonstrated that CNCP directly activated TRPC6 channels by increasing channel open probability with an EC50 value of 6.01 μM. Considered together, these data demonstrate that the direct activation of TRPC6 channels contributes to CNCP-induced apoptotic cell death in HK-2 cells. Our data point out the potential risk of renal toxicity from CNCP if used as a therapeutic agent.