TRPC6-dependent Ca2+ signaling mediates airway inflammation in response to oxidative stress via ERK pathway

Abstract

Ozone (O 3) plays an extremely important role in airway inflammation by generating reactive oxygen species (ROS) including hydrogen peroxide, then promoting redox actions and causing oxidative stress. Evidences indicate that TRPC6 (canonical transient receptor potential channel 6) is a redox-regulated Ca 2+ permeable nonselective cation channel, but its role in the setting of oxidative stress-related airway inflammation remains unknown. Here, we found that both TRPC6 −/− mice and mice pretreated with SAR7334, a potent TRPC6 inhibitor, were protected from O 3-induced airway inflammatory responses. In vitro, both knockdown of TRPC6 expression with shRNA and TRPC6 blockage markedly attenuated the release of cytokines IL-6 and IL-8 induced by O 3 or H 2 O 2 in 16HBE cells (human bronchial epithelial cell line). Treatment with O 3 or H 2 O 2 enhanced TRPC6 protein expression in vivo and vitro. We also observed that TRPC6-dependent increase of intracellular Ca 2+ concentration ([Ca 2+ ] i) was triggered by H 2 O 2 , which consisted of the release from intracellular calcium store and the influx of extracellular Ca 2+ and could be further strengthened by 6-h O 3 exposure in both 16HBE cells and HBEpiCs (primary human bronchial epithelial cells). Moreover, we confirmed that the activation of MAPK signals (ERK1/2, p38, JNK) was required for the inflammatory response induced by O 3 or H 2 O 2 while only the phosphorylation of ERK pathway was diminished in the TRPC6knockdown situation. These results demonstrate that oxidative stress regulates TRPC6-mediated Ca 2+ cascade, which leads to the activation of ERK pathway and inflammation and could become a potential target to treat oxidative stressassociated airway inflammatory diseases.

Oxidative Stress in Ozone-Induced Chronic Lung Inflammation and Emphysema: A Facet of Chronic Obstructive Pulmonary Disease

“…Oxidative stress induces TRPC6 expression and function in podocytes ( 36 ), HEK293T cells ( 37 ), vascular myocytes ( 38 ), neutrophils ( 35 ), and macrophages ( 39 ). In a recent study, TRPC6 in bronchial epithelium cells, was shown to act as an oxidative stress sensor where the TRPC6-mediated calcium cascade leads to the activation of the extracellular signal-regulated kinase (ERK) pathway and inflammation ( 40 ). This could be a possible inflammatory response pathway in several cell types in response to ozone, but this has yet to be described in COPD.…”

Ion Channels Orchestrate Pancreatic Ductal Adenocarcinoma Progression and Therapy

“…TRPC6 is also expressed in PSCs, where it mediates hypoxia-induced migration and production of cytokines ( Nielsen et al, 2017 ). In a mouse model, it could be shown that inhibition of TRPC6 with specific antagonists (SAR7334, BI-749327) diminishes the inflammatory response in the lungs and ameliorates cardiac and renal fibrosis ( Lin et al, 2019 ; Chen et al, 2020 ). One can presume that such a beneficial effect could also be elicited in PDAC, in part by inhibiting neutrophil recruitment into the tumor.…”

TRPC6 Attenuates Cortical Astrocytic Apoptosis and Inflammation in Cerebral Ischemic/Reperfusion Injury

“…Evidence shows that TRPC6 is a crucial regulator of inflammatory cascades, especially in pulmonary inflammation (Chen et al, 2020 ; Ortiz-Muñoz et al, 2020 ). TRPC6 contributes to platelet activation, leukocyte transendothelial migration, lung vascular barrier disruption, and airway inflammation (Tauseef et al, 2012 ; Weber et al, 2015 ; Chen et al, 2020 ; Ortiz-Muñoz et al, 2020 ). In addition, activation of the TRPC6 channel promotes apoptosis in neonatal glomerular mesangial cells and renal tubular epithelial cells under different injury conditions (Soni and Adebiyi, 2016 ; Hou et al, 2018 ).…”