Abstract: SA-PO653
A Role for Circulating MicroRNAs in the Pathogenesis of IgA Nephropathy
Session Information
- Glomerular Diseases: IgA and Complement-Mediated GN
November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1302 Glomerular Diseases: Immunology and Inflammation
Authors
- Bhachu, Jasraj Singh, University of Leicester, Leicester, Leicestershire, United Kingdom
- Barratt, Jonathan, University of Leicester, Leicester, Leicestershire, United Kingdom
- Pawluczyk, Izabella Z.A., University of Leicester, Leicester, Leicestershire, United Kingdom
Background
IgA nephropathy (IgAN) is considered to be a systemic disease with the kidneys being injured as innocent bystanders, therefore investigating circulating mediators as a key to its pathogenesis is well founded. Recently, the emergence of microRNAs (miRs) as negative regulators of gene expression has opened new avenues to understand their role in normal and pathological processes. The aim of this study was to investigate the role of circulating miRs in IgAN.
Methods
Next generation sequencing (NGS) was performed by Qiagen (Germany) on sera from patients with IgAN, idiopathic membranous nephropathy (IMN) and healthy subjects (HS). NGS data was validated using independent serum samples from each cohort by RT-qPCR. Extracellular exosomes were also isolated from the sera and urine of patients and controls and miR expression measured by RT-qPCR. MicroRNA expression was also measured in peripheral blood mononuclear cells (PBMCs). Mechanistic studies were subsequently performed using kidney cells in vitro.
Results
NGS and subsequent validation using RT-qPCR identified miRs -483-5p and -122-5p as being significantly overexpressed in those IgAN patients at high risk of future progression (IgAN-HR) compared to those at low risk of progression (IgAN-LR) and HS, but not compared to IMN. Both miRs were also significantly increased in serum exosomes of IgAN-HR compared to IgAN-LR and HS and this time also compared to IMN. Sera from IgAN-HR patients contained significantly more exosomes than sera from IgAN-LR, HS and IMN. Exosomal miR-483-5p levels correlated with proteinuria and with serum-derived tumour necrosis factor (TNF) super family analytes in IgAN. Having identified that miR-483-5p was enriched in peripheral blood CD19+ cells and in the urine, in vitro studies showed that exposing immortalised B cells to TNFR1 resulted in B cell activation and release of B cell-derived exosomes containing high levels of miR-483-5p. Collecting duct epithelial cells (CDECs) exposed to these miR-483-5p-enriched B cell-derived exosomes adopted a pro-inflammatory phenotype which was mediated by the transcription factor SOCS3, a known target of miR-483-5p.
Conclusion
This study has identified a potential novel mechanism for the TNF superfamily/B cell-axis in driving tubulointerstitial injury in IgAN.
Funding
- Private Foundation Support