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

Abstract

Transient receptor potential canonical 6 (TRPC6) channel is an important non-selective cation channel with a variety of physiological roles in the central nervous system. Evidence has shown that TRPC6 is involved in the process of experimental stroke; however, the underlying mechanisms remain unclear. In the present study, the role of astrocytic TRPC6 was investigated in an oxygen–glucose deprivation cell model and middle cerebral artery occlusion (MCAO) mouse model of stroke. HYP9 (a selective TRPC6 agonist) and SKF96365 (SKF; a TRPC antagonist) were used to clarify the exact functions of TRPC6 in astrocytes after ischemic stroke. TRPC6 was significantly downregulated during ischemia/reperfusion (IR) injury in cultured astrocytes and in cortices of MCAO mice. Application of HYP9 in vivo alleviated the brain infarct lesion, astrocytes population, apoptosis, and interleukin-6 (IL-6) and IL-1β release in mouse cortices after ischemia. HYP9 dose-dependently inhibited the downregulation of TRPC6 and reduced astrocytic apoptosis, cytotoxicity and inflammatory responses in IR insult, whereas SKF aggravated the damage in vitro. In addition, modulation of TRPC6 channel diminished IR-induced Ca2+ entry in astrocytes. Furthermore, decreased Ca2+ entry due to TRPC6 contributed to reducing nuclear factor kappa light chain enhancer of activated B cells (NF-κB) nuclear translocation and phosphorylation. Overexpression of astrocytic TRPC6 also attenuated apoptosis, cytotoxicity, inflammatory responses, and NF-κB phosphorylation in modeled ischemia in astrocytes. The results of the present study indicate that the TRPC6 channel can act as a potential target to reduce both inflammatory responses and apoptosis in astrocytes during IR injury, subsequently attenuating ischemic brain damage. In addition, we provide a novel view of stroke therapy by targeting the astrocytic TRPC6 channel.

Role of TRPC6 in kidney damage after acute ischemic kidney injury

“…In addition, TRPC6 is involved in immune responses regulating transendothelial migration, chemotaxis, phagocytosis, and cytokine release 19 , 20 . A recent study using pharmacological blockage of TRPC6 in mice demonstrated that decreased Ca 2+ entry due to TRPC6 contributed to reducing astrocytic apoptosis, cytotoxicity and inflammatory responses in cerebral ischemic/reperfusion insult 30 . Given that, in the present study we hypothesized that TRPC6 inhibition may also exhibit nephroprotective effects in AKI.…”

Neuroprotective Effects of Omentin-1 Against Cerebral Hypoxia/Reoxygenation Injury via Activating GAS6/Axl Signaling Pathway in Neuroblastoma Cells

“…It is one of the mechanisms to maintain the stability of the internal environment ( Carneiro and El-Deiry, 2020 ). Evidence shows that neuronal apoptosis is the basic form of delayed neuronal death after cerebral IR ( Liu et al, 2020 ). Anti-apoptotic Bcl2 and pro-apoptotic Bax were determined to play key roles in cell survival or death ( Pihán et al, 2017 ).…”

Astrocytes as a Therapeutic Target in Alzheimer’s Disease–Comprehensive Review and Recent Developments

“…TRP canonical 6 (TRPC6), a non-selective cationic channel expressed in astrocytes with a plethora of functions in the CNS, has been implicated in the pathophysiology of AD and other pathological processes including neuroinflammation and ischemia [ 325 ]. Hyperforin, a TRPC6 agonist, can increase intracellular calcium levels, reduce astrogliosis and disaggregate Aβ aggregates, with effects on spatial memory [ 326 , 327 ].…”