The Role And Mechanism Of TRPV4 Regulating Endoplasmic Reticulum Stress And Inflammation In Parkinson’s Disease

Parkinson’s disease(PD)is a neurodegenerative disease,which is characterized by the loss of dopaminergic(DA)neurons in the substantia nigra(SN).Its molecular mechanism is still unclear and the treatments are unsatisfactory.Endoplasmic reticulum stress(ERS)and neuroinflammation are involved in PD.ERS can cause neurodegeneration and neuron loss.Meanwhile,inflammation also can cause neuron injury and apoptosisAs a member of transient receptor potential(TRP)receptor family,transient receptor potential vanilloid 4(TRPV4)is widely expressed in brain,lung,kidney,bladder and digestive tract.In the brain,TRPV4 channels are expressed in neurons,astrocytes,microglia,vascular endothelial cells and vascular smooth muscle cells Studies have shown that TRPV4 is related to the pathogenesis of Alzheimer’s disease,cerebral ischemia,brain tumor,epilepsy,trigeminal neuralgia and other nervous system diseases.Therefore,TRPV4 plays a crucial role in central nervous system(CNS),and it has the potential to become a novel therapeutic target for brain diseases.TRPV4 activates ERS by calcium induced calcium release(CICR)and mediates neuroinflammationTo study the role of TRPV4 in ERS and inflammation in PD,we used HC067047,a specific inhibitor of TRPV4,and TRPV4 siRNA to study the mechanism of TRPV4 in ERS of 1-methyl-4-phenylpyridinium ion(MPP+)-induced PC12 cells.Meanwhile,adeno-associated virus(AAV)was stereotaxically and bilaterally injected into the SN of C57BL/6 mice to construct upregulation or knockdown of TRPV4 mice.We investigated the role of TRPV4 in motor function and the DA neuron survival of the mice subsequently treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)We also detected the expressions of the ERS-associated molecules,including sarco/endoplasmic reticulum Ca2+-ATPase 2(SERCA2),glucose regulated protein 78(GRP78),glucose regulated protein 94(GRP94),C/EBP homologous protein(CHOP),pro-cysteinyl aspartate specific proteinase-12(procaspase-12),tyrosine hydroxylase(TH)and inflammatory factors,including interleukin-18(IL-18),cyclooxgenase-2(COX-2),5-lipoxygenase(5-LOX)and pro-cysteinyl aspartate specific proteinase-1(procaspase-1),to illustrate the mechanisms of TRPV4 regulating ERS and inflammation in SN of PD.The main results are as follows(1)TRPV4 specific inhibitor,HC067047 inhibited MPP+-induced ERS by decreasing GRP78,GRP94,CHOP and increasing SERCA2 and procaspase-12,and protected PC 12 cells from apoptosis and restored the expression of TH(2)TRPV4 siRNA inhibited MPP+-induced ERS by decreasing GRP78,GRP94,CHOP and increasing SERCA2 and procaspase-12,and protected PC 12 cells from apoptosis and restored the expression of TH(3)Knockdown of TRPV4 in SN significantly improved the motor dysfunction of PD mice,while upregulation of TRPV4 exacerbated the motor dysfunction of PD mice(4)Knockdown of TRPV4 in SN rescued the TH positive neuron of PD mice through decreasing GRP78,GRP94,CHOP and increasing the level of SERCA2 and procaspase-12,while upregulation of TRPV4 inversely regulated the above molecules(5)Knockdown of TRPV4 in SN alleviated inflammation of PD mice by decreasing the high levels of IL-18,COX-2,5-LOX and increasing procaspase-1,while upregulation of TRPV4 inversely regulated the above moleculesIn conclusion:TRPV4 mediated the motor functions of PD mice.TRPV4 regulated ERS and inflammation pathways to affect the loss of DA neurons in SN of PD mice.Therefore,TRPV4 played an important regulatory role in the development of PD,and it had the potential to be a target for preventing and treating PD.