Acid‐sensing ion channel 1a is involved in ischaemia/reperfusion induced kidney injury by increasing renal epithelia cell apoptosis

Abstract

Acidic microenvironment is commonly observed in ischaemic tissue. In the kidney, extracellular pH dropped from 7.4 to 6.5 within 10 minutes initiation of ischaemia. Acid‐sensing ion channels (ASICs) can be activated by pH drops from 7.4 to 7.0 or lower and permeates to Ca 2+ entrance. Thus, activation of ASIC1a can mediate the intracellular Ca 2+ accumulation and play crucial roles in apoptosis of cells. However, the role of ASICs in renal ischaemic injury is unclear. The aim of the present study was to test the hypothesis that ischaemia increases renal epithelia cell apoptosis through ASIC1a‐mediated calcium entry. The results show that ASIC1a distributed in the proximal tubule with higher level in the renal tubule ischaemic injury both in vivo and in vitro. In vivo, Injection of ASIC1a inhibitor PcTx‐1 previous to ischaemia/reperfusion (I/R) operation attenuated renal ischaemic injury. In vitro, HK‐2 cells were pre‐treated with PcTx‐1 before hypoxia, the intracellular concentration of Ca 2+ , mitochondrial transmembrane potential (∆ψm) and apoptosis was measured. Blocking ASIC1a attenuated I/R induced Ca 2+ overflow, loss of ∆ψm and apoptosis in HK‐2 cells. The results revealed that ASIC1a localized in the proximal tubular and contributed to I/R induced kidney injury. Consequently, targeting the ASIC1a may prove to be a novel strategy for AKI patients.

Acid-Sensing Ion Channels and Mechanosensation

“…Blockade of ASIC1a channels in the proximal tubule attenuated Ca 2+ influx in instances of renal ischemic reperfusion and led to decreased levels of human proximal tubular cell apoptosis, indicating that ASIC1a contributes to reperfusion-induced injuries in the kidney [ 66 ]. In the brain, our studies have shown that disruption of either ASIC1 or ASIC2 genes exerted neuroprotection against ischemic brain injury [ 28 , 67 ].…”

Animal toxins — Nature’s evolutionary-refined toolkit for basic research and drug discovery

“…The different properties of PcTx1 and Hi1a broaden the pharmacological toolkit for studying ASIC1a and ASIC1a-related pathologies. Together these two venom peptides have provided striking pharmacological evidence that ASIC1a is involved in ischemic injuries of not just the brain, but also the heart [156] and kidney [157].…”

White matter injury in the neonatal hypoxic‐ischemic brain and potential therapies targeting microglia

“…OPCs and OLs from OGD-induced cell death in vitro, and these effects may be mediated by STAT3, a key transcription factor (Dai et al, 2020). Importantly, IL-4 promotes OL regeneration and repairs WM integrity in stroke models (Liu et al, 2016;Song et al, 2019).…”

“…For instance, TGF‐α secreted by microglia directly protects OPCs and OLs from OGD‐induced cell death in vitro , and these effects may be mediated by STAT3, a key transcription factor (Dai et al., 2020). Importantly, IL‐4 promotes OL regeneration and repairs WM integrity in stroke models (Liu et al., 2016; Song et al., 2019). Knockout of IL‐4 in experimental models leads to WM deterioration while the intranasal administration of IL‐4 nanoparticles after stroke improves WM integrity and results in superior long‐term functional recovery in wild‐type mice (Song et al., 2019).…”

“…Importantly, IL‐4 promotes OL regeneration and repairs WM integrity in stroke models (Liu et al., 2016; Song et al., 2019). Knockout of IL‐4 in experimental models leads to WM deterioration while the intranasal administration of IL‐4 nanoparticles after stroke improves WM integrity and results in superior long‐term functional recovery in wild‐type mice (Song et al., 2019). The injection of IL‐10, a potent stimulator of M2 microglial polarization, exerts a neuroprotective effect on newborn mice with a cystic preterm brain injury (Mesples et al., 2003).…”