Effect of ER stress on sphingolipid levels and apoptotic pathways in retinal pigment epithelial cells

Afşar, Ebru; Konuk, Esma Kirimlioglu; Çeker, Tuğçe; Yılmaz, Çağatay; Demır, Necdet; Aslan, Mutay

doi:10.1016/j.redox.2020.101430

Cited by 21 publications

(8 citation statements)

References 47 publications

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“…As the de novo synthesis of ceramide occurs in the ER [ 37 ], ceramide synthesis may be altered as a result of the loss of protein homeostasis within the ER. It has recently been shown that chemically induced ER stress in human retinal pigment epithelium cells leads to increased ceramide levels, along with increased levels of pro-apoptotic factors [ 3 ]. Alpha-synuclein accumulation can cause ER stress and inhibition of ER–Golgi trafficking, leading to cytotoxicity [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Altered ceramide metabolism is a feature in the extracellular vesicle-mediated spread of alpha-synuclein in Lewy body disorders

et al. 2021

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Mutations in glucocerebrosidase (GBA) are the most prevalent genetic risk factor for Lewy body disorders (LBD)—collectively Parkinson’s disease, Parkinson’s disease dementia and dementia with Lewy bodies. Despite this genetic association, it remains unclear how GBA mutations increase susceptibility to develop LBD. We investigated relationships between LBD-specific glucocerebrosidase deficits, GBA-related pathways, and α-synuclein levels in brain tissue from LBD and controls, with and without GBA mutations. We show that LBD is characterised by altered sphingolipid metabolism with prominent elevation of ceramide species, regardless of GBA mutations. Since extracellular vesicles (EV) could be involved in LBD pathogenesis by spreading disease-linked lipids and proteins, we investigated EV derived from post-mortem cerebrospinal fluid (CSF) and brain tissue from GBA mutation carriers and non-carriers. EV purified from LBD CSF and frontal cortex were heavily loaded with ceramides and neurodegeneration-linked proteins including alpha-synuclein and tau. Our in vitro studies demonstrate that LBD EV constitute a “pathological package” capable of inducing aggregation of wild-type alpha-synuclein, mediated through a combination of alpha-synuclein–ceramide interaction and the presence of pathological forms of alpha-synuclein. Together, our findings indicate that abnormalities in ceramide metabolism are a feature of LBD, constituting a promising source of biomarkers, and that GBA mutations likely accelerate the pathological process occurring in sporadic LBD through endolysosomal deficiency.

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Section: Discussionmentioning

confidence: 99%

Altered ceramide metabolism is a feature in the extracellular vesicle-mediated spread of alpha-synuclein in Lewy body disorders

et al. 2021

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“…Our results support previous studies that have shown a buildup of CER during ER stress. 33 To our knowledge, this is the first study to report increased CER levels in a rat model of ER stress created by TM treatment. Exogenous CER causes inhibition of sarcoplasmic/endoplasmic reticulum Ca 2+ - ATPase (SERCA) ensuing [Ca 2+ ] depletion in the ER.…”

Section: Discussionmentioning

confidence: 79%

Organ function, sphingolipid levels and inflammation in tunicamycin induced endoplasmic reticulum stress in male rats

et al. 2020

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Disorders of the endoplasmic reticulum (ER) lead to cellular damage but can cause cell death if ER dysfunction is prolonged. We aimed to examine liver/kidney functions, neutral sphingomyelinase (N-SMase) activity, sphingolipid levels, cytosolic phospholipase A2 (cPLA2) and cyclooxygenase-2 (COX-2) protein expression in rats under ER stress. ER stress was induced by tunicamycin (TM) and the ER stress inhibitor taurodeoxycholic acid (TUDCA) was injected before induction of ER stress. ER stress was confirmed by increased tissue levels of GRP78. Hematological and biochemical profiles were measured by autoanalyzers while hepatic and renal injury was evaluated via microscopy and histopathological scoring. Tissue levels of C16-C24 sphingomyelins (SM), C16-C24 ceramides (CERs) and sphingosine-1-phosphate (S1P) were determined by LC-MS/MS. Tissue cPLA2 and COX-2 were measured by western blot and activity assays. Tunicamycin treatment caused kidney and liver function test abnormalities, increased hematocrit and hemoglobin levels but decreased white blood cell counts. Histopathological findings showed hepatic necroinflammation and renal tubular damage in rats treated with TM. TUDCA administration attenuated WBC abnormalities and TM- induced hepatic/renal functional impairment in ER stress, as evident by significantly restored serum ALT, AST, creatinine, and total bilirubin levels. A significant increase was observed in N-SMase activity, tissue levels of C16-C24 CERs, cPLA2 and COX-2 expression in liver and kidney tissue under ER stress. TUDCA administration decreased tissue CER levels, cPLA2 and COX-2 expression as well as prostaglandin E2 (PGE2) formation. These results signify that ER stress causes hepatic and renal toxicity as well as CER-induced PGE2 formation in liver and kidney.

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“…Pharmacological inhibition of fatty acid-binding protein 4 (FABP4) reduce renal tubular epithelial cell damage induced by rhabdomyolysis via inhibiting ERS [14]. Although animal and cell culture studies have revealed evident bene cial of ERS regulation or inhibition via chemical reagent inhibitor like TUDCA and 4-PBA [5,28,29], further application of these reagents were largely limited due to shortness of safety data.…”

Section: Discussionmentioning

confidence: 99%

VDR attenuate ischemia-reperfusion kidney injury via inhibiting ERS effector protein ATF4

Tang

Dai

et al. 2022

Preprint

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Activating transcription factor 4 (ATF4) is one of the key effectors of endoplasmic reticulum stress (ERS), ATF4/CHOP pathway mediated ERS plays an important role in the progression of acute kidney disease (AKI). We have previously reported that Vitamin D receptor (VDR) exert renoprotection in rodent AKI models. However, whether ATF4 as well as ERS is involved in the protective effect of VDR in ischemia-reperfusion (I/R) induced AKI unknown. Herein, we showed that VDR agonist paricalcitol and VDR overexpression alleviated I/R induced renal injury and cells apoptosis with decreased ATF4 and attenuated ERS, while VDR deletion significantly resulted in further increased ATF4, more drastic ERS and renal injury in I/R mice models. In addition, paricalcitol remarkably reduced tunicamycin™ induced ATF4 and ERS with attenuated renal injury, while VDR deletion aggravated the above changes in TM mice models. Moreover, overexpression of ATF4 partially abolished the effect of paricalcitol against TM-induced ERS and apoptosis, while inhibition of ATF4 enhanced the protective effect of paricalcitol. Bioinformatics analysis indicated potential VDR binding sites on ATF4 promotor sequence which were further confirmed by ChIP-qPCR and dual-luciferase reporter gene assay. In conclusion, VDR attenuated I/R-induced AKI through suppressing ERS partly via transcriptional regulation of ATF4.

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Effect of ER stress on sphingolipid levels and apoptotic pathways in retinal pigment epithelial cells

Cited by 21 publications

References 47 publications

Altered ceramide metabolism is a feature in the extracellular vesicle-mediated spread of alpha-synuclein in Lewy body disorders

Altered ceramide metabolism is a feature in the extracellular vesicle-mediated spread of alpha-synuclein in Lewy body disorders

Organ function, sphingolipid levels and inflammation in tunicamycin induced endoplasmic reticulum stress in male rats

VDR attenuate ischemia-reperfusion kidney injury via inhibiting ERS effector protein ATF4

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