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首页> 外文期刊>American Journal of Physiology >Effect of BSA-induced ER stress on SGLT protein expression levels and alpha-MG uptake in renal proximal tubule cells.
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Effect of BSA-induced ER stress on SGLT protein expression levels and alpha-MG uptake in renal proximal tubule cells.

机译：BSA诱导的内质网应激对肾近端小管细胞中SGLT蛋白表达水平和α-MG摄取的影响。

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Recent studies demonstrated that endoplasmic reticulum (ER) stress regulates glucose homeostasis and that ER stress preconditioning which induces an adaptive, protective unfolded protein response (UPR) offers cytoprotection against nephrotoxins. Thus the aim of the present study was to use renal proximal tubule cells (PTCs) to further elucidate the link between the BSA-induced ER stress and alpha-methyl-d-glucopyranoside (alpha-MG) uptake and to identify related signaling pathways. Among ER stress inducers such as high glucose, BSA, H2O2, or tumicamycin, BSA pretreatment ameliorated the reduction of Na(+)-glucose cotransporter (SGLT) expression and alpha-MG uptake by gentamicin or cyclosporine A. Immunofluorescence studies revealed that BSA (10 mg/ml) stimulated the expression of glucose-regulated protein 78 (GRP78), an ER stress biomarker. In addition, BSA increased levels of GRP78 protein expression and eukaryotic initiation factor 2alpha (eIF2alpha) phosphorylation in a time-dependent manner. Furthermore, transfection with a GRP78-specific small interfering RNA (siRNA) inhibited BSA-stimulated SGLT expression and alpha-MG uptake. In experiments designed to unravel the mechanisms underlying BSA-induced ER stress, BSA stimulated the production of cellular reactive oxygen species (ROS), and antioxidants such as ascorbic acid or N-acetylcysteine (NAC) blocked BSA-induced increases in GRP78 activation, eIF2alpha phosphorylation, SGLT expression, and alpha-MG uptake. Moreover, the cells upregulated peroxisome proliferator-activated receptor-gamma (PPARgamma) mRNA levels in response to BSA or troglitazone (a PPARgamma agonist), but BSA was ineffective in the presence of GW9662 (a PPARgamma antagonist). In addition, both BSA and troglitazone stimulated GRP78 and eIF2alpha activation, SGLT expression, and alpha-MG uptake, whereas GW9662 inhibited the effects of BSA. BSA also stimulated phosphorylation of JNK and NF-kappaB, and GW9662 or GRP78 siRNA attenuated this response. Moreover, SP600125 or SN50 effectively blocked SGLT expression and alpha-MG uptake in BSA- or PPARgamma agonists (troglitazone or PGJ2)-treated PTCs. We conclude that BSA induces ER stress through ROS production and PPARgamma activation, which subsequently activates JNK/NF-kappaB signaling to enhance glucose uptake in renal PTCs.
机译：最近的研究表明，内质网（ER）应激调节葡萄糖稳态，而ER应激预处理可诱导适应性，保护性未折叠蛋白反应（UPR）提供针对肾毒素的细胞保护作用。因此，本研究的目的是使用肾近端肾小管细胞（PTC）进一步阐明BSA诱导的ER应激与α-甲基-d-吡喃葡萄糖苷（α-MG）摄取之间的联系，并确定相关的信号通路。在ER应激诱导剂中，例如高葡萄糖，BSA，H2O2或tumicamycin，BSA预处理可减轻庆大霉素或环孢霉素A的Na（+）-葡萄糖共转运蛋白（SGLT）表达和α-MG吸收的减少。免疫荧光研究表明，BSA（ 10 mg / ml）刺激了ER应激生物标记物葡萄糖调节蛋白78（GRP78）的表达。此外，BSA以时间依赖的方式增加了GRP78蛋白表达和真核起始因子2α（eIF2alpha）磷酸化的水平。此外，用GRP78特异性小干扰RNA（siRNA）转染可抑制BSA刺激的SGLT表达和α-MG摄取。在旨在揭示BSA诱导的ER应激的机制的实验中，BSA刺激了细胞活性氧（ROS）的产生，抗氧化剂例如抗坏血酸或N-乙酰半胱氨酸（NAC）阻止了BSA诱导的GRP78活化增加，eIF2alpha磷酸化，SGLT表达和α-MG摄取。此外，细胞响应BSA或曲格列酮（一种PPARgamma激动剂）上调了过氧化物酶体增殖物激活的受体-γ（PPARgamma）mRNA水平，但在GW9662（一种PPARgamma拮抗剂）存在下，BSA无效。另外，BSA和曲格列酮均刺激GRP78和eIF2alpha激活，SGLT表达和α-MG摄取，而GW9662抑制BSA的作用。 BSA还刺激了JNK和NF-κB的磷酸化，而GW9662或GRP78 siRNA减弱了这种反应。此外，SP600125或SN50在BSA或PPARγ激动剂（曲格列酮或PGJ2）处理的PTC中有效地阻断了SGLT表达和alpha-MG摄取。我们得出的结论是，BSA通过ROS产生和PPARgamma激活诱导ER应激，随后激活JNK / NF-kappaB信号来增强肾脏PTC中的葡萄糖摄取。

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