纳米颗粒介导的脯氨酰羟化酶结构域蛋白 2 小干扰 RNA 的肾靶向递送减轻了肾缺血/再灌注损伤。
Kidney-Targeted Delivery of Prolyl Hydroxylase Domain Protein 2 Small Interfering RNA with Nanoparticles Alleviated Renal Ischemia/Reperfusion Injury.
机构信息
Department of Pharmacology & Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (D.X., G.H., C.C., J.K.R., N.L.); College of Biomedical Engineering, Sichuan University, Chengdu, China (J.W.); Department of Chemical and Biochemical Engineering, Missouri University of Science and Technology, Rolla, Missouri (H.Y.); and Department of Chemistry, Virginia Commonwealth University, Richmond, Virginia (Y.Q.).
Department of Pharmacology & Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (D.X., G.H., C.C., J.K.R., N.L.); College of Biomedical Engineering, Sichuan University, Chengdu, China (J.W.); Department of Chemical and Biochemical Engineering, Missouri University of Science and Technology, Rolla, Missouri (H.Y.); and Department of Chemistry, Virginia Commonwealth University, Richmond, Virginia (Y.Q.)
出版信息
J Pharmacol Exp Ther. 2021 Sep;378(3):235-243. doi: 10.1124/jpet.121.000667. Epub 2021 Jun 8.
Inhibition of hypoxia-inducible factor-prolyl hydroxylase (PHD) has been shown to protect against various kidney diseases. However, there are controversial reports on the effect of PHD inhibition in renoprotection. The present study determined whether delivery of PHD2 small interfering RNA (siRNA) using an siRNA carrier, folic acid (FA)-decorated polyamidoamine dendrimer generation 5 (G5-FA), would mainly target kidneys and protect against renal ischemia/reperfusion injury (I/R). The renal I/R was generated by clipping the renal pedicle for 30 minutes in uninephrectomized mice. Mice were sacrificed 48 hours after I/R. Normal saline or G5-FA complexed with control or PHD2 siRNA was injected via tail vein 24 hours before ischemia. After the injection of near-infrared fluorescent dye-labeled G5-FA, the fluorescence was mainly detected in kidneys but not in other organs. The reduction of PHD2 mRNA and protein was only observed in kidneys but not in other organs after injection of PHD2-siRNA-G5-FA complex. The injection of PHD2-siRNA-G5-FA significantly alleviated renal I/R injury, as shown by the inhibition of increases in serum creatinine and blood urea nitrogen, the blockade of increases in kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin, and the improvement of histologic damage compared with mice treated with control siRNA. PHD2 siRNA can be delivered specifically into kidneys using G5-FA, and that local knockdown of PHD2 gene expression within the kidney alleviates renal I/R injury. Therefore, G5-FA is an efficient siRNA carrier to deliver siRNA into the kidney, and that local inhibition of PHD2 within the kidney may be a potential strategy for the management of acute I/R injury. SIGNIFICANCE STATEMENT: Folic acid (FA)-decorated polyamidoamine dendrimer generation 5 (G5-FA) was demonstrated to be an effective carrier to deliver small interfering RNA (siRNA) into kidneys. Delivery of prolyl hydroxylase domain protein 2 siRNA with G5-FA effectively protected the kidneys against the acute renal ischemia/reperfusion injury.
抑制缺氧诱导因子脯氨酰羟化酶（PHD）已被证明可预防各种肾脏疾病。然而，关于 PHD 抑制在肾脏保护中的作用存在争议报告。本研究旨在确定使用小干扰 RNA（siRNA）载体叶酸（FA）修饰的聚酰胺胺树枝状大分子 G5-FA 递送 PHD2siRNA 是否主要靶向肾脏并预防肾缺血/再灌注损伤（I/R）。在单侧肾切除的小鼠中夹闭肾蒂 30 分钟以产生肾 I/R。在 I/R 后 48 小时处死小鼠。在缺血前 24 小时通过尾静脉注射生理盐水或与对照或 PHD2siRNA 复合的 G5-FA。注射近红外荧光染料标记的 G5-FA 后，荧光主要在肾脏中检测到，但在其他器官中未检测到。仅在注射 PHD2-siRNA-G5-FA 复合物后在肾脏中观察到 PHD2mRNA 和蛋白的减少，但在其他器官中未观察到。与用对照 siRNA 处理的小鼠相比，注射 PHD2-siRNA-G5-FA 可显著减轻肾 I/R 损伤，表现为血清肌酐和血尿素氮的增加受到抑制，肾损伤分子 1 和中性粒细胞明胶酶相关脂质运载蛋白的增加受到阻断，以及与用对照 siRNA 处理的小鼠相比，组织学损伤得到改善。使用 G5-FA 可以将 PHD2siRNA 特异性递送至肾脏，并且肾脏内 PHD2 基因表达的局部敲低可减轻肾 I/R 损伤。因此，G5-FA 是将 siRNA 递送至肾脏的有效 siRNA 载体，并且肾脏内 PHD2 的局部抑制可能是急性 I/R 损伤管理的潜在策略。意义声明：已证明叶酸（FA）修饰的聚酰胺胺树枝状大分子 G5-FA 是将小干扰 RNA（siRNA）递送至肾脏的有效载体。用 G5-FA 递送脯氨酰羟化酶结构域蛋白 2siRNA 可有效保护肾脏免受急性肾缺血/再灌注损伤。
Zotero 插件