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Data on exosomal-derived urinary miRNAs have identified several miRNAs associated with disease activity and fibrosis formation, but studies on prognosis are lacking. We conducted a qPCR array screening on urinary exosomes from 14 patients with biopsy-proven proliferative lupus glomerulonephritis with a renal outcome of clinical response (<i>n</i> = 7) and non-response (<i>n</i> = 7) following therapy. Validation studies were performed by qRT-PCR in a new lupus nephritis (LN) cohort (responders = 22 and non-responders = 21). Responder patients expressed significantly increased levels of miR-31, miR-107, and miR-135b-5p in urine and renal tissue compared to non-responders. MiR-135b exhibited the best predictive value to discriminate responder patients (area under the curve = 0.783). In vitro studies showed exosome-derived miR-31, miR-107, and miR-135b-5p expression to be mainly produced by tubular renal cells stimulated with inflammatory cytokines (e.g IL1, TNF&#945;, IFN&#945; and IL6). Uptake of urinary exosomes from responders by mesangial cells was superior compared to that from non-responders (90% vs. 50%, <i>p</i> &lt; 0.0001). <i>HIF1A</i> was identified as a potential common target, and low protein levels were found in non-responder renal biopsies. <i>HIF1A</i> inhibition reduced mesangial proliferation and <i>IL-8</i>, <i>CCL2</i>, <i>CCL3</i>, and <i>CXCL</i>1 mesangial cell production and <i>IL-6/VCAM-1</i> in endothelial cells. Urinary exosomal miR-135b-5p, miR-107, and miR-31 are promising novel markers for clinical outcomes, regulating LN renal recovery by <i>HIF1A</i> inhibition.