Exosomal mitochondrial tRNAs and miRNAs as potential predictors of inflammation in renal proximal tubular epithelial cells

Glory Ranches; Maximilian Zeidler; Roman Kessler; Martina Hoelzl; Michael W Hess; Jonathan Vosper; Paul Perco; Herbert Schramek; Kai K Kummer; Michaela Kress; Anne Krogsdam; Michael Rudnicki; Gert Mayer; Alexander Huettenhofer

doi:10.1016/j.omtn.2022.04.035

Exosomal mitochondrial tRNAs and miRNAs as potential predictors of inflammation in renal proximal tubular epithelial cells

Mol Ther Nucleic Acids. 2022 May 4:28:794-813. doi: 10.1016/j.omtn.2022.04.035. eCollection 2022 Jun 14.

Authors

Affiliations

¹ Division of Genomics and RNomics, Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria.
² Institute of Physiology, Medical University of Innsbruck, Innsbruck 6020, Austria.
³ Institute of Histology and Embryology, Medical University of Innsbruck, Innsbruck 6020, Austria.
⁴ Division of Medical Biochemistry, Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria.
⁵ Department of Internal Medicine IV (Nephrology and Hypertension), Medical University of Innsbruck, Innsbruck 6020, Austria.
⁶ Division of Bioinformatics, Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria.

Abstract

Exosomes have emerged as a valuable repository of novel biomarkers for human diseases such as chronic kidney disease (CKD). From a healthy control group, we performed microRNA (miRNA) profiling of urinary exosomes and compared it with a cell culture model of renal proximal tubular epithelial cells (RPTECs). Thereby, a large fraction of abundant urinary exosomal miRNAs could also be detected in exosomes derived from RPTECs, indicating them as a suitable model system for investigation of CKD. We subsequently analyzed exosomes from RPTECs in pro-inflammatory and pro-fibrotic states, mimicking some aspects of CKD. Following cytokine treatment, we observed a significant increase in exosome release and identified 30 dysregulated exosomal miRNAs, predominantly associated with the regulation of pro-inflammatory and pro-fibrotic-related pathways. In addition to miRNAs, we also identified 16 dysregulated exosomal mitochondrial RNAs, highlighting a pivotal role of mitochondria in sensing renal inflammation. Inhibitors of exosome biogenesis and release significantly altered the abundance of selected candidate miRNAs and mitochondrial RNAs, thus suggesting distinct sorting mechanisms of different non-coding RNA (ncRNA) species into exosomes. Hence, these two exosomal ncRNA species might be employed as potential indicators for predicting the pathogenesis of CKD and also might enable effective monitoring of the efficacy of CKD treatment.

Keywords: MT: Oligonucleotides: Diagnostics and Biosensors; biomarkers; chronic kidney disease; cytokines; exosomes; inflammation and fibrosis; miRNAs; mtRNAs; ncRNAs; renal proximal tubular epithelial cells.