Journal of the American Society of Nephrology ( IF 10.3 ) Pub Date : 2021-10-01 , DOI: 10.1681/asn.2020111561 Tao-Tao Tang 1 , Bin Wang , Zuo-Lin Li , Yi Wen , Song-Tao Feng , Min Wu , Dan Liu , Jing-Yuan Cao , Qing Yin , Di Yin , Yu-Qi Fu , Yue-Ming Gao , Zhao-Ying Ding , Jing-Yi Qian , Qiu-Li Wu , Lin-Li Lv , Bi-Cheng Liu
AKI is a significant public health problem with high morbidity and mortality. Unfortunately, no definitive treatment is available for AKI. RNA interference (RNAi) provides a new and potent method for gene therapy to tackle this issue.
We engineered red blood cell–derived extracellular vesicles (REVs) with targeting peptides and therapeutic siRNAs to treat experimental AKI in a mouse model after renal ischemia/reperfusion (I/R) injury and unilateral ureteral obstruction (UUO). Phage display identified peptides that bind to the kidney injury molecule-1 (Kim-1). RNA-sequencing (RNA-seq) characterized the transcriptome of ischemic kidney to explore potential therapeutic targets.
REVs targeted with Kim-1–binding LTH peptide (REVLTH) efficiently homed to and accumulated at the injured tubules in kidney after I/R injury. We identified transcription factors P65 and Snai1 that drive inflammation and fibrosis as potential therapeutic targets. Taking advantage of the established REVLTH, siRNAs targeting P65 and Snai1 were efficiently delivered to ischemic kidney and consequently blocked the expression of P-p65 and Snai1 in tubules. Moreover, dual suppression of P65 and Snai1 significantly improved I/R- and UUO-induced kidney injury by alleviating tubulointerstitial inflammation and fibrosis, and potently abrogated the transition to CKD.
A red blood cell–derived extracellular vesicle platform targeted Kim-1 in acutely injured mouse kidney and delivered siRNAs for transcription factors P65 and Snai1, alleviating inflammation and fibrosis in the tubules.
中文翻译:
Kim-1 靶向细胞外囊泡:RNAi 治疗 AKI 的新治疗平台
AKI 是一个具有高发病率和死亡率的重大公共卫生问题。不幸的是,AKI 尚无明确的治疗方法。RNA 干扰 (RNAi) 为基因治疗提供了一种新的有效方法来解决这个问题。
我们设计了具有靶向肽和治疗性 siRNA 的红细胞来源的细胞外囊泡 (REV),以治疗小鼠模型中肾缺血/再灌注 (I/R) 损伤和单侧输尿管梗阻 (UUO) 后的实验性 AKI。噬菌体展示鉴定出与肾损伤分子 1 (Kim-1) 结合的肽。RNA 测序 (RNA-seq) 表征了缺血性肾脏的转录组,以探索潜在的治疗靶点。
I/R 损伤后,以 Kim-1 结合 LTH 肽 (REV LTH ) 为靶标的 REV 有效地归巢并聚集在肾脏受损的小管处。我们确定了驱动炎症和纤维化的转录因子P65和Snai1作为潜在的治疗靶点。利用已建立的 REV LTH,靶向P65和Snai1的 siRNA被有效地递送至缺血肾脏,从而阻断肾小管中 P-p65 和 Snai1 的表达。此外, P65和Snai1的双重抑制通过减轻肾小管间质炎症和纤维化,显着改善 I/R 和 UUO 引起的肾损伤,并有效地阻止向 CKD 的转变。
红细胞来源的细胞外囊泡平台以急性损伤的小鼠肾脏中的 Kim-1 为靶点,并为转录因子P65和Snai1递送 siRNA,从而减轻小管中的炎症和纤维化。