1. Kim-1 Targeted Extracellular Vesicles: A New Therapeutic Platform for RNAi to Treat AKI
- Author
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Zhao-ying Ding, Song-Tao Feng, Qing Yin, Bi-Cheng Liu, Zuo-Lin Li, Bin Wang, Tao-Tao Tang, Qiu-Li Wu, Dan Liu, Yi Wen, Jing-Yi Qian, Jing-Yuan Cao, Di Yin, Lin-Li Lv, Yu-Qi Fu, Min Wu, and Yueming Gao
- Subjects
Male ,Erythrocytes ,Genetic enhancement ,Inflammation ,Extracellular Vesicles ,Mice ,Fibrosis ,medicine ,Animals ,Hepatitis A Virus Cellular Receptor 1 ,RNA, Small Interfering ,Kidney ,Renal ischemia ,business.industry ,Transcription Factor RelA ,Acute kidney injury ,Genetic Therapy ,General Medicine ,Extracellular vesicle ,Acute Kidney Injury ,medicine.disease ,Disease Models, Animal ,Kidney Tubules ,Basic Research ,medicine.anatomical_structure ,Nephrology ,Reperfusion Injury ,Cancer research ,RNA Interference ,Snail Family Transcription Factors ,medicine.symptom ,Peptides ,business ,Ureteral Obstruction ,Kidney disease - Abstract
Background: Acute kidney injury (AKI) is a significant public health problem with high morbidity and mortality. Unfortunately, no definitive treatment is currently available for AKI. RNA interference (RNAi) provides a new and potent method for gene therapy to tackle this dilemma. Methods We engineered red blood cell-derived extracellular vesicles (REVs) with targeting peptides and therapeutic siRNAs to treat experimental AKI in a mouse model following 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. Results REVs targeted with Kim-1-binding LTH peptide (REVLTH) efficiently homed to and accumulated at the injured tubules in kidney following 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 chronic kidney disease. Conclusions 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.
- Published
- 2021