Identification and analysis of the predictive urinary exosomal miR-195-5p in lupus nephritis based on renal miRNA-mRNA co-expression network

Abstract

Objective Lupus nephritis (LN) is the main complication of systemic lupus erythematosus (SLE), causing huge financial burden and poor quality of life. Due to the low compliance of renal biopsy, we aim to find a non-invasive biomarker of LN to optimize its predictive, preventive, and personalized medical service or management. Method Herein, we provided a bioinformatic screen combined clinical validation strategy for rapidly mining exosomal miRNAs for LN diagnosis and management. We screened out differentially expressed miRNAs (DEMs) and differentially expressed mRNAs (DEGs) in LN database and performed a miRNA-mRNA integrated analysis to select out reliable changed miRNAs in LN tissues by using R and Cytoscape. Urinary exosomes were collected by ultracentrifugation and analyzed by nano-tracking analysis and western blotting. Detection of aquaporin-2 showed the tubular source of urinary exosomes. Urinary exosomal miRNAs were detected by RT-qPCR and the target of miR-195-5p was verified by using bioinformatic, dual-luciferase, and western blotting. Result 15 miRNAs and their 60 target mRNAs were contained in miRNA-mRNA integrated map. Bioinformatic analysis showed these miRNAs were involved in various cellular biological process. Exosomal miR-195-5p, miR-25-3p, miR-429, and miR-218-5p were verified in a small clinical group (n = 47). Urinary exosomal miR-195-5p, miR-25-3p, and miR-429 were downregulated in patients and miR-195-5p could recognize LN patients from SLE with good sensitivity and specificity, showing good potential in LN disease monitoring and diagnosis. Conclusion We analyzed and obtained a series of differential miRNAs in LN kidney tissues and suggested that urinary exosomal miR-195-5p could serve as a novel biomarker in LN. Further, miR-195-5p-CXCL10 axis could be a therapeutic target of LN.

Exosomal miRNAs in autoimmune skin diseases

“…Chen et al (39) found that exosomes derived from umbilical cord blood-derived MSCs could alleviate diffuse alveolar hemorrhage in SLE mice and demonstrated that exosomes from umbilical cord blood-derived MSCs could transport miR-146-5p to target and inhibit the expression of NOTCH1, thus promoting the polarization of M2 macrophages, leading to the suppression of excessive inflammatory responses and protection against alveolar injury. Cheng et al (40) demonstrated downregulation of miR-195-5p in the urine of lupus nephritis patients and its negative modulation of CXCL10, consistent with their initial result based on online available data. Furthermore, this miRNA was negatively correlated with urinary protein, renal damage, serum complement levels, and disease severity.…”

Urinary Extracellular Vesicles in Chronic Kidney Disease: From Bench to Bedside?

“…The identification of relevant miRNAs involved in LN kidney recovery may aid in the development of new therapeutic approaches [83]. Urinary exosomal miR-195-5p, miR-25-3p, and miR-429 were all downregulated in patients, and miR-195-5p was able to distinguish LN patients from SLE with high sensitivity and specificity, indicating a promising future for LN disease monitoring and diagnosis [87]. Let-7a and miR-21, two miRs known to be differentially expressed in LN tissues and/or serum, were downregulated in urinary exosomes during an active flare of LN [88].…”

Decipher the Immunopathological Mechanisms and Set Up Potential Therapeutic Strategies for Patients with Lupus Nephritis

“…Perez-Hernandez et al [ 151 ] further discovered that urinary exosomal miR-146a was not only serving as a biomarker of albuminemia, correlating with lupus activity, proteinuria, and histological features to discriminate individual LN patients, but also represented as a good baseline marker for SLE flares. Cheng et al [ 152 ] used a bioinformatic screen combined with clinical validation to rapidly extract the exosomal miRs for an LN diagnosis and management. The group screened out differentially expressed miRs and mRNAs in the LN database.…”

“…Urinary exosomal miRs: miR-29c for early renal fibrosis [ 147 ] miR-21, miR-29c, miR-150 for early renal fibrosis [ 148 ] miR-21↓ and let-7c↓ for LN disease flare [ 149 ] miR-135p for treatment responder patients [ 150 ] miR-146a for disease flare [ 151 ] miR-195-5p as disease biomarker [ 152 ] …”