Abstract
While urine-based liquid biopsy has expanded to the analyses of extracellular nucleic acids, the potential of transfer RNA (tRNA) encapsulated within extracellular vesicles has not been explored as a new class of urine biomarkers for kidney injury. Using rat kidney and mouse tubular cell injury models, we tested if extracellular vesicle-loaded tRNA and their m1A (N1-methyladenosine) modification reflect oxidative stress of kidney injury and determined the mechanism of tRNA packaging into extracellular vesicles. We determined a set of extracellular vesicle-loaded, isoaccepting tRNAs differentially released after ischemia–reperfusion injury and oxidative stress. Next, we found that m1A modification of extracellular vesicle tRNAs, despite an increase of the methylated tRNAs in intracellular vesicles, showed little or no change under oxidative stress. Mechanistically, oxidative stress decreases tRNA loading into intracellular vesicles while the tRNA-loaded vesicles are accumulated due to decreased release of the vesicles from the cell surface. Furthermore, Maf1-mediated transcriptional repression of the tRNAs decreases the cargo availability for extracellular vesicle release in response to oxidative stress. Taken together, our data support that release of extracellular vesicle tRNAs reflects oxidative stress of kidney tubules which might be useful to detect ischemic kidney injury and could lead to rebalance protein translation under oxidative stress.
Highlights
While urine-based liquid biopsy has expanded to the analyses of extracellular nucleic acids, the potential of transfer RNA encapsulated within extracellular vesicles has not been explored as a new class of urine biomarkers for kidney injury
To examine the global relationship between the abundance of transfer RNA (tRNA) in urinary vesicles and the progression of acute kidney injury, we re-analyzed our previous small RNA-sequencing d ata[14] and determined changes in abundance of tRNAs released through urinary vesicles during an extended period of time following renal ischemic injury (Fig. 1)
The presence of a significant fraction of urinary vesicle tRNAs in mapped sequence read counts[14] led us to test the hypothesis that the levels of tRNAs in urinary extracellular vesicle might reflect acute kidney injury
Summary
While urine-based liquid biopsy has expanded to the analyses of extracellular nucleic acids, the potential of transfer RNA (tRNA) encapsulated within extracellular vesicles has not been explored as a new class of urine biomarkers for kidney injury. Our data support that release of extracellular vesicle tRNAs reflects oxidative stress of kidney tubules which might be useful to detect ischemic kidney injury and could lead to rebalance protein translation under oxidative stress. Ala Arg Asn Asp Cys Gln Glu Gly His Ile Leu Lys Met Phe Pro Sec Ser Thr Trp Tyr Val isoacceptor tRNA tRNAs are ubiquitous small non-coding RNAs that link the genetic information transcribed in mRNA to protein translation[16]. They have long been considered as a simple adaptor molecule in protein synthesis delivering amino acids to translating ribosomes. Given the abundance of tRNAs in urinary vesicles as well as stress-regulated tRNA biogenesis, we here asked whether cellular stress alters transport of tRNAs to the extracellular space through vesicle traffic and extracellular release of tRNA packaged in vesicles might report injured kidney state
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