Cilostazol ameliorates ischemia/reperfusion‐induced tight junction disruption in brain endothelial cells by inhibiting endoplasmic reticulum stress

Alport syndrome is a hereditary progressive chronic kidney disease caused by mutations in type IV collagen genes COL4A3/4/5. X-linked Alport syndrome (XLAS) is caused by mutations in the COL4A5 gene and is the most common form of Alport syndrome. A strong correlation between the type of COL4A5 mutation and the age developing endstage renal disease in male patients has been found. Mutation to the a (IV) chain causes retention of the protein to the endoplasmic reticulum lumen, which causes endoplasmic reticulum stress (ERS) and subsequent exertion of deleterious intracellular effects through the activation of ERS. The exact time point that mutant type IV collagen a chain exerts its deleterious effects remains elusive. In this study, we explored the relationship between the COL4A5 genotype and cell type in ERS activation. We obtained skin fibroblasts from Alport syndrome patients with different COL4A5 mutation categories [i.e., a missense mutation (c.4298G > T, p.Gly1433Val) in exon 47, a splicing mutation (c.1949-1G > A) in intron 25 and an insertion (c.573_c.574insG, p. Pro193Alafs*23) in exon 10], and then reprogrammed these fibroblasts into induced pluripotent stem cells (iPSCs). Interestingly, no significant dysregulation of ERS pathway markers was observed for the three COL4A5 mutant iPSCs; however, significant activation of ERS in COL4A5 mutant fibroblasts was observed. In addition, we found that the activation levels of some ERS markers in fibroblasts varied among the three COL4A5 mutation types. Mutant COL4A5 proteins were demonstrated to have different effects on cells at different stages of ontogenesis, providing a theoretical basis for choosing the timing of intervention. The observed differences in activation of ERS by the COL4A5 mutant fibroblasts may contribute to the intracellular molecular mechanisms that describe the correlation between genotype and clinical features in XLAS.

Section: Discussionsupporting

confidence: 87%

Endoplasmic Reticulum Stress Activation in Alport Syndrome Varies Between Genotype and Cell Type

Liang

Xing

et al. 2020

Front. Genet.

“…For example, ER stress was verified to be involved in Reticulon Protein 1-C-mediated cerebral I/R injury in MCAO rats (Gong et al 2017 ). Nan et al demonstrated that inhibiting ER stress was the mechanism of cilostazol relieving cerebral I/R injury-induced endothelial cell damage (Nan et al 2019 ). Therefore, ER stress inhibition can be an effective therapeutic strategy for cerebral I/R injury.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the severe and continued ER stress may result in increased transcription of CHOP, an essential molecule in the apoptotic signaling pathway, and then trigger apoptosis (Tsai et al 2018 ). Previous studies suggested that attenuating ER stress could effectively relieve cerebral I/R injury (Feng et al 2019 ; Nan et al 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Acupuncture protects against cerebral ischemia–reperfusion injury via suppressing endoplasmic reticulum stress-mediated autophagy and apoptosis

Líu

et al. 2020

Mol Med

Background Acupuncture treatment possesses the neuroprotection potential to attenuate cerebral ischemia–reperfusion (I/R) injury. Endoplasmic reticulum (ER) stress has been suggested to be involved in the pathogenic mechanism of cerebral I/R injury. Whether acupuncture protects against cerebral I/R injury via regulating ER stress remains unclear. This study aimed to evaluate the role of ER stress in the neuroprotection of acupuncture against cerebral I/R injury and its underlying mechanisms. Methods Cerebral I/R injury was induced by middle cerebral artery occlusion (MCAO) in rats. Acupuncture was carried out at Baihui (GV 20), and Qubin (GB7) acupoints in rats immediately after reperfusion. The infarct volumes, neurological score, ER stress, autophagy and apoptosis were determined. Results Acupuncture treatment decreased infarct volume, neurological score and suppressed ER stress via inactivation of ATF-6, PERK, and IRE1 pathways in MCAO rats. Attributing to ER stress suppression, 4-PBA (ER stress inhibitor) promoted the beneficial effect of acupuncture against cerebral I/R injury. Whereas, ER stress activator tunicamycin significantly counteracted the neuroprotective effects of acupuncture. In addition, acupuncture restrained autophagy via regulating ER stress in MCAO rats. Finally, ER stress took part in the neuroprotective effect of acupuncture against apoptosis in cerebral I/R injury. Conclusions Our findings suggest that acupuncture offers neuroprotection against cerebral I/R injury, which is attributed to repressing ER stress-mediated autophagy and apoptosis.

“…For example, ER stress was veri ed to be involved in Reticulon Protein 1-C-mediated cerebral I/R injury in MCAO rats (Gong et al 2017). Nan et al demonstrated that inhibiting ER stress was the mechanism of cilostazol relieving cerebral I/R injury-induced endothelial cell damage (Nan et al 2019). Therefore, ER stress inhibition can be an effective therapeutic strategy for cerebral I/R injury.…”

Section: Discussionmentioning

confidence: 99%

Acupuncture protects against cerebral ischemia-reperfusion injury via suppressing endoplasmic reticulum stress-mediated autophagy and apoptosis

Líu

et al. 2020

Preprint

Background: Acupuncture treatment possesses the neuroprotection potential to attenuate cerebral ischemia-reperfusion (I/R) injury. Endoplasmic reticulum (ER) stress has been suggested to be involved in the pathogenic mechanism of cerebral I/R injury. Whether acupuncture protects against cerebral I/R injury via regulating ER stress remains unclear. This study aimed to evaluate the role of ER stress in the neuroprotection of acupuncture against cerebral I/R injury and its underlying mechanisms. Methods: Cerebral I/R injury was induced by middle cerebral artery occlusion (MCAO) in rats. Acupuncture was carried out at Baihui (GV 20), Hegu (L14), and Taichong (Liv3) acupoints in rats immediately after reperfusion. The infarct volumes, neurological score, ER stress, autophagy and apoptosis were determined. Results: Acupuncture treatment decreased infarct volume, neurological score and suppressed ER stress via inactivation of ATF-6, PERK, and IRE1 pathways in MCAO rats. Attributing to ER stress suppression, 4-PBA (ER stress inhibitor) promoted the beneficial effect of acupuncture against cerebral I/R injury. Whereas, ER stress activator tunicamycin significantly counteracted the neuroprotective effects of acupuncture. In addition, acupuncture restrained autophagy via regulating ER stress in MCAO rats. Finally, ER stress took part in the neuroprotective effect of acupuncture against apoptosis in cerebral I/R injury. Conclusions: Our findings suggest that acupuncture offers neuroprotection against cerebral I/R injury, which is attributed to repressing ER stress-mediated autophagy and apoptosis.