Transfer RNA Fragments in the Kidney in Hypertension

Abstract

Supplemental Digital Content is available in the text. Small noncoding RNAs (sncRNAs) are important regulators of gene expression. In contrast with well-studied microRNAs, transfer RNA-derived RNA fragments (tRFs) are a new class of sncRNAs that has not been studied in hypertension. This study aims to characterize renal tRFs and identify dysregulation and potential role of renal tRFs in hypertension. We analyzed sncRNA-sequencing and mRNA-sequencing data from the kidneys of Dahl salt-sensitive rats and sncRNA-sequencing data from kidney biopsy specimens from hypertensive nephrosclerosis patients. Over 300 tRFs were identified in the rat renal outer medulla, several of which were differentially expressed between rats with different levels of salt sensitivity or between rats on low- and high-salt diets. The number and abundance of these tRFs were comparable with those of well-known microRNAs. Multiple tRFs were potentially involved in the regulation of immune function, cell cycle, ion transport, and metabolic pathways based on an integrative analysis of sncRNA-sequencing and mRNA-sequencing data from the same set of rats. As a proof of concept, we experimentally validated the gene regulatory effect of a 3′-tRF (3′-tRF-ProTGG-19) that was dysregulated in both salt-induced hypertension in rats (P=0.002) and hypertensive nephrosclerosis in humans (P=1.7×10−05). To our knowledge, our study represents the first characterization of tRFs in hypertension. These findings demonstrate the abundant expression of tRFs in human and rat kidneys and pave the way for studies to investigate novel roles of renal tRFs in the development of hypertension and renal injury.