Low circulating miR-190a-5p predicts progression of chronic kidney disease.

Abstract

MicroRNAs (miRs) have the potential to be employed as diagnostic and prognostic biomarkers of chronic kidney disease (CKD) and are functionally important in disease pathogenesis. To identify novel miR biomarkers we performed small RNA-sequencing (sRNA-Seq) that were quantitatively altered in the circulation of individuals with type 2 diabetes (T2D) with CKD compared to those with normal kidney function. MiR-190a-5p abundance was significantly lower in the circulation of T2D patients with reduced kidney function compared to those with normal kidney function. To validate if the loss of circulating miR-190a-5p was associated with reduced kidney function we measured miR-190a-5p in an unselected cohort of CKD patients and determined if dysregulated miR-190a-5p could predict kidney outcomes. In individuals with no or moderate albuminuria (<300mg/mmol), serum miR-190a-5p levels predicted CKD progression (reaching end-stage kidney disease or >30% reduction from baseline eGFR, independent of age, sex, baseline eGFR, urinary albumin excretion, or blood pressure (adjusted HR 0.80, 95% CI: 0.66-0.96, p=0.015). To identify the kidney source of miR-190a-5p we utilised transcriptomic data from mouse models of kidney injury and single nuclear (sn) RNA-Seq from human kidney, finding that miR-190a-5p is enriched in the proximal tubule (PT) but down-regulated following injury. Bioinformatic analysis highlighted ADAM10as a potential miR-190a-5p target and we validated this in human PT cell line. Our analyses suggest that miR-190a-5p is a biomarker of tubular cell health and low circulating levels may predict CKD progression in patients with low or moderate proteinuria independent of existing risk factors.