Dataset Information

STF-083010, an inhibitor of XBP1 splicing, attenuates acute renal failure in rats by suppressing endoplasmic reticulum stress-induced apoptosis and inflammation.

ABSTRACT: Endoplasmic reticulum (ER) stress is one of the driving forces of ischemia/reperfusion (IR)-induced acute renal failure (ARF). STF-083010, an inhibitor of the endonuclease activity of inositol-requiring enzyme-1 (IRE1), has the potential to block the initiation of a prolonged unfolded protein response (UPR) that is stimulated by ER stress and alleviates the impairments due to ER stress. In the current study, it was hypothesized that STF-083010 was capable of ameliorating ER stress-related damages in IR-induced ARF. Rats were administrated with STF-083010 and were subjected to induction of ARF using a ligation method. Then the effect of STF-083010 administration on the renal structure and function, oxidative stress, and inflammation in model rats was assessed. Furthermore, the levels of expression of UPR members and downstream effectors regulating apoptosis were detected as well. The results showed that establishment of the ARF model induced ER stress and impaired the renal structure and function. Administration of STF-083010 ameliorated impairments in the structure and function of the kidneys and the effect was associated with the suppressed oxidative stress and inflammation. At the molecular level, STF-083010 inhibited the prolonged UPR by downregulating the expressions of GRP78, p-IRE1, XBP1s, CHOP, and caspase 3, partially explaining the decreased apoptotic rate. The current study evaluated the potential of STF-083010 in treating ER stress-induced symptoms in ARF for the first time, and the findings demonstrated that STF-083010 resulted in effective treatment outcomes of ARF.

SUBMITTER: Liu L

PROVIDER: S-EPMC6083033 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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STF-083010, an inhibitor of XBP1 splicing, attenuates acute renal failure in rats by suppressing endoplasmic reticulum stress-induced apoptosis and inflammation.

Liu Lei L Xu Lu L Zhang Shaoqing S Wang Dong D Dong Guoxia G Chen Hanwen H Li Xinjian X Shu Chi C Wang Rong R

Experimental animals 20180425 3

Endoplasmic reticulum (ER) stress is one of the driving forces of ischemia/reperfusion (IR)-induced acute renal failure (ARF). STF-083010, an inhibitor of the endonuclease activity of inositol-requiring enzyme-1 (IRE1), has the potential to block the initiation of a prolonged unfolded protein response (UPR) that is stimulated by ER stress and alleviates the impairments due to ER stress. In the current study, it was hypothesized that STF-083010 was capable of ameliorating ER stress-related damage ...[more]

PMID: 29695649

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Project description:Endoplasmic reticulum (ER) stress and apoptotic cell death play an important role in the pathogenesis and perpetuation of inflammatory bowel disease (IBD). We aimed to explore the potential of glutamine to reduce ER stress and apoptosis in a rat model of experimental IBD. Colitis was induced in male Wistar rats by intracolonic administration of 30 mg of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Glutamine (25 mg/dL) was given by rectal route daily for 2 d or 7 d. Both oxidative stress (TBARS concentration and oxidised/reduced glutathione ratio) and ER stress markers (CHOP, BiP, calpain-1 and caspase-12 expression) increased significantly within 48 h of TNBS instillation, and glutamine attenuated the extent of the changes. Glutamine also inhibited the significant increases of ATF6, ATF4 and spliced XBP-1 mRNA levels induced by TNBS instillation. TNBS-colitis resulted in a significant increase in p53 and cytochrome c expression, and a reduced Bcl-xL expression and Bax/Bcl-2 ratio. These effects were significantly inhibited by glutamine. Treatment with the amino acid also resulted in significant decreases of caspase-9, caspase-8 and caspase-3 activities. Double immunofluorescence staining showed co-localization of CHOP and cleaved caspase-3 in colon sections. Phospho-JNK and PARP-1 expression was also significantly higher in TNBS-treated rats, and treatment with glutamine significantly decreased JNK phosphorylation and PARP-1 proteolysis. To directly address the effect of glutamine on ER stress and apoptosis in epithelial cells, the ER stress inducers brefeldin A and tunicamycin were added to Caco-2 cells that were treated with glutamine (5 mM and 10 mM). The significant enhancement in PERK, ATF6 phosphorylated IRE1, BiP and cleaved caspase-3 expression induced by brefeldin A and tunicamycin was partly prevented by glutamine. Data obtained indicated that modulation of ER stress signalling and anti-apoptotic effects contribute to protection by glutamine against damage in TNBS-induced colitis.

Project description:BackgroundPalmitic acid (PA), the main component of dietary saturated fat, causes apoptosis in many cell types, including mouse granulosa cell. Melatonin, an important endogenous hormone, has beneficial effects on female reproductive processes. Since elevated PA levels are present in follicular fluid (FF) of patients with infertility and are shown to be toxic for granulosa cells, we investigated the molecular mechanisms of PA toxicity in mouse granulosa cells and explored the effects of melatonin on PA-induced apoptosis.MethodsGranulosa cells from immature female mice were cultured for 24 h in medium containing PA and/or melatonin. Then, the effects of PA alone or combined with melatonin on viability, apoptosis and endoplasmic reticulum (ER) stress in granulosa cells were detected by methyl thiazolyl tetrazolium (MTT) assay, flow cytometry assay and western blot. After 48 h of PA and/or melatonin treatment, the concentrations of estradiol (E2) and progesterone (P4) in the culture supernatants were measured with ELISA kits.ResultsIn this study, we explored the effects of melatonin on cell viability and apoptosis in PA-treated mouse granulosa cells and uncovered the signaling pathways involved in these processes. Our results showed that 200-800 μM PA treatment reduces cell viability, induces cell apoptosis, enhances the expression of apoptosis-related genes (Caspase 3 and B-cell lymphoma-2 (BCL-2) associated X protein (BAX)), and activates the expression of ER stress marker genes (glucose-regulated protein 78 (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP)). Melatonin treatment (1-10 μM) suppresses 400 μM PA-induced cell viability decrease, cell apoptosis, Caspase 3 activation, and BAX, CHOP, and GRP78 expression. In addition, we found that 10 μM melatonin successfully attenuated the 400 μM PA-induced estrogen (E2) and progesterone (P4) decreases.ConclusionsThis study suggests that PA triggers cell apoptosis via ER stress and that melatonin protects cells against apoptosis by inhibiting ER stress in mouse granulosa cells.

Dataset Information

STF-083010, an inhibitor of XBP1 splicing, attenuates acute renal failure in rats by suppressing endoplasmic reticulum stress-induced apoptosis and inflammation.

Publications

STF-083010, an inhibitor of XBP1 splicing, attenuates acute renal failure in rats by suppressing endoplasmic reticulum stress-induced apoptosis and inflammation.

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