Abstract
For lupus nephritis (LN) management, it is very important to detect fibrosis at an early stage. Urinary exosomal miRNAs profiling can be used as a potential multi-marker phenotyping tool to identify early fibrosis. We isolated and characterised urinary exosomes and cellular pellets from patients with biopsy-proven LN (n = 45) and healthy controls (n = 20). LN chronicity index (CI) correlated with urinary exosomal miR-21, miR-150, and miR-29c (r = 0.565, 0.840, −0.559, respectively). This miRNA profile distinguished low CI from moderate-high CI in LN patients with a high sensitivity and specificity (94.4% and 99.8%). Furthermore, this multimarker panel predicted an increased risk of progression to end-stage renal disease (ESRD). Pathway analysis identified VEGFA and SP1 as common target genes for the three miRNAs. Immunohistochemistry in LN renal biopsies revealed a significant increase of COL1A1 and COL4A1 correlated with renal chronicity. SP1 decreased significantly in the high-CI group (p = 0.002). VEGFA levels showed no differences. In vitro experiments suggest that these miRNA combinations promote renal fibrosis by increasing profibrotic molecules through SP1 and Smad3/TGFβ pathways. In conclusion, a urinary exosomal multimarker panel composed of miR-21, miR-150, and miR-29c provides a non-invasive method to detect early renal fibrosis and predict disease progression in LN.
Highlights
Fibrosis, or tissue scarring, is the result of an excessive, persistent, and destructive accumulation of extracellular matrix components (ECM) in response to chronic tissue injury in the kidney
No significant clinical differences were observed between subgroups such as age, gender, serum creatinine, proteinuria, blood urea nitrogen (BUN), and estimated glomerular filtration rate (eGFR) (Table 1)
We have shown that urinary exosomes are the best source of urinary miRNA biomarkers in Lupus nephritis (LN)
Summary
Tissue scarring, is the result of an excessive, persistent, and destructive accumulation of extracellular matrix components (ECM) in response to chronic tissue injury in the kidney. Renal fibrosis represents the final stage of most chronic kidney diseases and contributes to a progressive and irreversible decline in kidney function. The continuous accumulation of ECM causes a disruption of the epithelium and/or endothelium integrity that results in the activation of a complex cascade of molecular and cellular events [1]. Despite improvements in its management, up to 20% of patients will progress to end-stage renal disease (ESRD) [5]. Detection of early stages of fibrosis could contribute to identify patients at risk of progressing to ESRD who can benefit from new therapeutic
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