B cell-derived exosomal miR-483-5p and its potential role in promoting kidney function loss in IgA nephropathy.

Abstract

While mesangial IgA deposition is the pathognomonic feature of IgA nephropathy (IgAN), the extent of mesangial IgA accumulation does not correlate with the future risk of kidney failure. This has led to the search for other serum factors that may influence clinical outcome. The emergence of microRNAs (miRs) as negative regulators of gene expression and the increasingly recognized role of extracellular miRs in intercellular communication has prompted study of the influence of miRs on inflammatory and scarring pathways in the kidneys. Here, next generation sequencing and subsequent qPCR validation identified a significant increase in the serum levels of miR-483-5p, largely packaged within exosomes. Levels of miR-483-5p in serum exosomes were greatest in those IgAN patients with higher levels of proteinuria who subsequently developed kidney failure. Exosomal miR-483-5p content significantly correlated with numerous soluble isoforms of the tumor necrosis factor (TNF) receptor super family suggesting lymphocytes as a source of the miR-enriched exosomes. In PBMC miR-483-5p expression was almost exclusively seen in CD19⁺ lymphocytes. Activation of a human IgA secreting B-cell line with soluble TNFR1 induced miR-483-5p synthesis and enrichment within exosomes. Exposure to miR-483-5p-enriched B cell exosomes resulted in a proinflammatory phenotypic change in cultured human collecting duct epithelial cells, likely mediated through suppression of the transcription factor SOCS3. miR-483-5p-enriched exosomes were also present in the urine of patients with IgAN. Interaction of B lymphocyte-derived miR-enriched exosomes with tubular epithelial cells may provide an explanation for the progressive tubulointerstitial scarring and loss of kidney function seen in IgAN.