McMaster University and St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada.
Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
PLoS One. 2021 Nov 30;16(11):e0260519. doi: 10.1371/journal.pone.0260519. eCollection 2021.
Endoplasmic reticulum (ER) stress is associated with acute kidney injury (AKI) caused by various mechanisms, including antibiotics, non-steroidal anti-inflammatory drugs, cisplatin, and radiocontrast. Tunicamycin (TM) is a nucleoside antibiotic that induces ER stress and is a commonly used model of AKI. 4-phenylbutyrate (4-PBA) is a chemical chaperone and histone deacetylase (HDAC) inhibitor and has been shown to protect the kidney from ER stress, apoptosis, and structural damage in a tunicamycin model of AKI. The renal protection provided by 4-PBA is attributed to its ability to prevent misfolded protein aggregation and inhibit ER stress; however, the HDAC inhibitor effects of 4-PBA have not been examined in the TM-induced model of AKI. As such, the main objective of this study was to determine if histone hyperacetylation provides any protective effects against TM-mediated AKI. The FDA-approved HDAC inhibitor vorinostat was used, as it has no ER stress inhibitory effects and therefore the histone hyperacetylation properties alone could be investigated. In vitro work demonstrated that vorinostat inhibited histone deacetylation in cultured proximal tubular cells but did not prevent ER stress or protein aggregation induced by TM. Vorinostat induced a significant increase in cell death, and exacerbated TM-mediated total cell death and apoptotic cell death. Wild type male mice were treated with TM (0.5 mg/kg, intraperitoneal injection), with or without vorinostat (50 mg/kg/day) or 4-PBA (1 g/kg/day). Mice treated with 4-PBA or vorinostat exhibited similar levels of histone hyperacetylation. Expression of the pro-apoptotic protein CHOP was induced with TM, and not inhibited by vorinostat. Further, vorinostat did not prevent any renal damage or decline in renal function caused by tunicamycin. These data suggest that the protective mechanisms found by 4-PBA are primarily due to its molecular chaperone properties, and the HDAC inhibitors used did not provide any protection against renal injury caused by ER stress.
内质网（ER）应激与各种机制引起的急性肾损伤（AKI）有关，包括抗生素、非甾体抗炎药、顺铂和造影剂。衣霉素（TM）是一种核苷抗生素，可诱导 ER 应激，是 AKI 的常用模型。4-苯丁酸（4-PBA）是一种化学伴侣和组蛋白去乙酰化酶（HDAC）抑制剂，已被证明可在 TM 诱导的 AKI 模型中保护肾脏免受 ER 应激、细胞凋亡和结构损伤。4-PBA 提供的肾脏保护归因于其防止错误折叠蛋白聚集和抑制 ER 应激的能力；然而，4-PBA 的 HDAC 抑制剂作用尚未在 TM 诱导的 AKI 模型中进行检查。因此，本研究的主要目的是确定组蛋白过度乙酰化是否对 TM 介导的 AKI 提供任何保护作用。使用了已获 FDA 批准的 HDAC 抑制剂伏立诺他，因为它没有 ER 应激抑制作用，因此可以单独研究组蛋白过度乙酰化的特性。体外研究表明，伏立诺他抑制培养的近端肾小管细胞中的组蛋白去乙酰化，但不能预防 TM 诱导的 ER 应激或蛋白聚集。伏立诺他诱导细胞死亡显著增加，并加重 TM 介导的总细胞死亡和凋亡细胞死亡。野生型雄性小鼠用 TM（0.5mg/kg，腹腔注射）处理，并用或不用伏立诺他（50mg/kg/天）或 4-PBA（1g/kg/天）处理。用 4-PBA 或伏立诺他处理的小鼠表现出相似水平的组蛋白过度乙酰化。TM 诱导了促凋亡蛋白 CHOP 的表达，而伏立诺他并未抑制其表达。此外，伏立诺他不能预防 TM 引起的任何肾脏损伤或肾功能下降。这些数据表明，4-PBA 发现的保护机制主要归因于其分子伴侣特性，而使用的 HDAC 抑制剂并未为 ER 应激引起的肾脏损伤提供任何保护。
