Department of Medicine, Division of Nephrology, McMaster University and St. Joseph's Healthcare Hamilton, Hamilton, Canada.
Department of Medicine, Division of Respirology, McMaster University and St. Joseph's Healthcare Hamilton, Hamilton, Canada.
PLoS One. 2014 Jan 8;9(1):e84663. doi: 10.1371/journal.pone.0084663. eCollection 2014.
Different forms of acute kidney injury (AKI) have been associated with endoplasmic reticulum (ER) stress; these include AKI caused by acetaminophen, antibiotics, cisplatin, and radiocontrast. Tunicamycin (TM) is a nucleoside antibiotic known to induce ER stress and is a commonly used inducer of AKI. 4-phenylbutyrate (4-PBA) is an FDA approved substance used in children who suffer from urea cycle disorders. 4-PBA acts as an ER stress inhibitor by aiding in protein folding at the molecular level and preventing misfolded protein aggregation. The main objective of this study was to determine if 4-PBA could protect from AKI induced by ER stress, as typified by the TM-model, and what mechanism(s) of 4-PBA's action were responsible for protection. C57BL/6 mice were treated with saline, TM or TM plus 4-PBA. 4-PBA partially protected the anatomic segment most susceptible to damage, the outer medullary stripe, from TM-induced AKI. In vitro work showed that 4-PBA protected human proximal tubular cells from apoptosis and TM-induced CHOP expression, an ER stress inducible proapoptotic gene. Further, immunofluorescent staining in the animal model found similar protection by 4-PBA from CHOP nuclear translocation in the tubular epithelium of the medulla. This was accompanied by a reduction in apoptosis and GRP78 expression. CHOP(-/-) mice were protected from TM-induced AKI. The protective effects of 4-PBA extended to the ultrastructural integrity of proximal tubule cells in the outer medulla. When taken together, these results indicate that 4-PBA acts as an ER stress inhibitor, to partially protect the kidney from TM-induced AKI through the repression of ER stress-induced CHOP expression.
不同形式的急性肾损伤（AKI）与内质网（ER）应激有关；这些包括由对乙酰氨基酚、抗生素、顺铂和放射造影剂引起的 AKI。衣霉素（TM）是一种已知能诱导 ER 应激的核苷抗生素，是一种常用的 AKI 诱导剂。4-苯丁酸（4-PBA）是一种已获美国食品和药物管理局批准的物质，用于治疗患有尿素循环障碍的儿童。4-PBA 通过在分子水平上辅助蛋白质折叠并防止错误折叠的蛋白质聚集，作为 ER 应激抑制剂发挥作用。本研究的主要目的是确定 4-PBA 是否可以预防 ER 应激诱导的 AKI，如 TM 模型所示，以及 4-PBA 作用的机制是什么负责保护。C57BL/6 小鼠用生理盐水、TM 或 TM 加 4-PBA 处理。4-PBA 部分保护了最易受损伤的解剖节段，即外髓质条纹，免受 TM 诱导的 AKI。体外研究表明，4-PBA 可保护人近端肾小管细胞免受凋亡和 TM 诱导的 CHOP 表达，CHOP 是一种 ER 应激诱导的促凋亡基因。此外，动物模型中的免疫荧光染色发现，4-PBA 可防止 CHOP 核转位进入髓质肾小管上皮细胞，从而提供类似的保护。这伴随着凋亡和 GRP78 表达的减少。CHOP（-/-）小鼠免受 TM 诱导的 AKI 保护。4-PBA 的保护作用延伸至外髓质近端肾小管细胞的超微结构完整性。综上所述，这些结果表明，4-PBA 作为 ER 应激抑制剂，通过抑制 ER 应激诱导的 CHOP 表达，部分保护肾脏免受 TM 诱导的 AKI。
