Abstract
Small noncoding RNAs, miRNAs (miRNAs), are emerging as important modulators in the pathogenesis of kidney disease, with potential as biomarkers of kidney disease onset, progression, or therapeutic efficacy. Bulk tissue small RNA-sequencing (sRNA-Seq) and microarrays are widely used to identify dysregulated miRNA expression but are limited by the lack of precision regarding the cellular origin of the miRNA. In this study, we performed cell-specific sRNA-Seq on tubular cells, endothelial cells, PDGFR-β+ cells, and macrophages isolated from injured and repairing kidneys in the murine reversible unilateral ureteric obstruction model. We devised an unbiased bioinformatics pipeline to define the miRNA enrichment within these cell populations, constructing a miRNA catalog of injury and repair. Our analysis revealed that a significant proportion of cell-specific miRNAs in healthy animals were no longer specific following injury. We then applied this knowledge of the relative cell specificity of miRNAs to deconvolute bulk miRNA expression profiles in the renal cortex in murine models and human kidney disease. Finally, we used our data-driven approach to rationally select macrophage-enriched miR-16-5p and miR-18a-5p and demonstrate that they are promising urinary biomarkers of acute kidney injury in renal transplant recipients.
Highlights
Small noncoding microRNAs are important both as key pathogenic regulators [1, 2] and as biomarkers of renal disease [3]
The aim of the study was to identify miRNAs that stringently remained enriched in specific cell types across acute injury, late injury, and repair in the kidney, which could be reasonably applied as cell-enriched markers in both acute kidney injury and chronic kidney disease
In order to identify cell-selective miRNAs, we chose to examine the sRNA profile of 4 of the key cell types implicitly involved in kidney injury and repair
Summary
Small noncoding microRNAs (miRNAs) are important both as key pathogenic regulators [1, 2] and as biomarkers of renal disease [3]. Their capacity to drive renal disease has been recognized and begun to be translated from preclinical studies [4, 5] to clinical trials of miRNA inhibitor–based (anti-miR) therapies in renal disease [6]. The expression of a given miRNA in such whole-tissue transcriptomics reflects both the abundance of that miRNA in each cell type and the proportion of that cell type within the sample [13] This is problematic both for disease process and for biomarker research, as the proportion of each renal cell type may vary considerably among renal health, injury, and repair. It is evident that inflammatory renal disease induces a large increase in the ratio of inflammatory cells to tubular cells as compared with that in a healthy kidney [14, 15]
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