P0970EXOSOMAL MIR-92A-1-5P DERIVED FROM PROXIMAL TUBULAR EPITHELIAL CELLS INDUCES EPITHELIAL-MESENCHYMAL TRANSITION IN MESANGIAL CELLS IN DIABETIC NEPHROPATHY

Abstract

Abstract Background and Aims Diabetic nephropathy (DN) has been the leading cause of end-stage renal disease in the world-wide. Exosomes play a key role in signal transduction between cell-cell communication in kidney pathophysiology. The aim of this study is to investigate that HK-2 cells-derived exosomal miR-92a-1-5p causes epithelial-mesenchymal transition (EMT) in mesangial cells (MCs), further leading to DN progression. Method The function of HK-2 cells-derived exosomes under normal glucose (NG) and high glucose (HG) was analyzed in mouse MCs model. Total RNAs were extracted from renal proximal tubular epithelial cells (RPTECs) of normal individual and type 2 diabetes for small RNA expression profiling using next-generation sequencing (NGS), then analyzed using systematic bioinformatics analyses. The expression of miR-92a-1-5p was examined in HK-2 cells-derived exosomes and MCs treated with HK-2 cells-derived exosomes under HG. The role of miR-92a-1-5p in EMT was evaluated using MCs model under NG and HG conditions. Urinary exosomal miR-92a-1-5p levels were measured in 50 type 2 diabetic patients and 34 healthy volunteers who were enrolled to determine the relationship between urinary exosomal miR-92a-1-5p and kidney function. Results Decreased E-cadherin, and increased N-cadherin and Vimentin expression were found in mouse MCs treated with HK-2 cells-derived exosomes under HG. Transcriptome analysis of RPTECs of normal individual and type 2 diabetic patient indicated that miR-92a-1-5p contributes to HG-induced renal proliferation. HG elevated miR-92a-1-5p expression in HK-2 cells and exosomes derived from-HK-2 cells, at meanwhile exosomal miR-92a-1-5p derived from-HK-2 cells under HG leads to EMT in mouse MCs. miR-92a-1-5p mimic increased EMT in mouse MCs under NG, and miR-92a-1-5p inhibitor reversed EMT in mouse MCs induced by exosomes derived from HK-2 cells under HG. EMT of mouse MCs was enhanced in the presence of exosomes isolated from the urine of type 2 diabetic patients with high levels of exosomal miR-92a-1-5p. Type 2 diabetic patients had higher urinary exosomal miR-92a-1-5p levels than normal individuals. Higher urinary exosomal miR-92a-1-5p levels were significantly correlated with lower renal function and higher albuminuria in human model. Conclusion Exosomal miR-92a-1-5p derived from HK-2 cells under HG induces EMT in mesangial cells. Blocking miR-92a-1-5p epigenetic regulatory network might be a potential therapeutic strategy to prevent EMT in DN.