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Lipotoxicity-Induced PRMT1 Exacerbates Mesangial Cell Apoptosis via Endoplasmic Reticulum Stress.

ABSTRACT: Lipotoxicity-induced mesangial cell apoptosis is implicated in the exacerbation of diabetic nephropathy (DN). Protein arginine methyltransferases (PRMTs) have been known to regulate a variety of biological functions. Recently, it was reported that PRMT1 expression is increased in proximal tubule cells under diabetic conditions. However, their roles in mesangial cells remain unexplored. Thus, we examined the pathophysiological roles of PRMTs in mesangial cell apoptosis. Treatment with palmitate, which mimics cellular lipotoxicity, induced mesangial cell apoptosis via protein kinase RNA-like endoplasmic reticulum kinase (PERK) and ATF6-mediated endoplasmic reticulum (ER) stress signaling. Palmitate treatment increased PRMT1 expression and activity in mesangial cells as well. Moreover, palmitate-induced ER stress activation and mesangial cell apoptosis was diminished by PRMT1 knockdown. In the mice study, high fat diet-induced glomerular apoptosis was attenuated in PRMT1 haploinsufficient mice. Together, these results provide evidence that lipotoxicity-induced PRMT1 expression promotes ER stress-mediated mesangial cell apoptosis. Strategies to regulate PRMT1 expression or activity could be used to prevent the exacerbation of DN.

SUBMITTER: Park MJ

PROVIDER: S-EPMC5535913 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Lipotoxicity-Induced PRMT1 Exacerbates Mesangial Cell Apoptosis via Endoplasmic Reticulum Stress.

Park Min-Jung MJ Han Ho Jae HJ Kim Dong-Il DI

International journal of molecular sciences 20170703 7

Lipotoxicity-induced mesangial cell apoptosis is implicated in the exacerbation of diabetic nephropathy (DN). Protein arginine methyltransferases (PRMTs) have been known to regulate a variety of biological functions. Recently, it was reported that PRMT1 expression is increased in proximal tubule cells under diabetic conditions. However, their roles in mesangial cells remain unexplored. Thus, we examined the pathophysiological roles of PRMTs in mesangial cell apoptosis. Treatment with palmitate, ...[more]

PMID: 28671608

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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.

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Lipotoxicity-Induced PRMT1 Exacerbates Mesangial Cell Apoptosis via Endoplasmic Reticulum Stress.

Publications

Lipotoxicity-Induced PRMT1 Exacerbates Mesangial Cell Apoptosis via Endoplasmic Reticulum Stress.

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