Abstract
BACKGROUND: Diabetic nephropathy (DN) is an increasing threat to human health and regarded to be the leading cause of end-stage renal disease worldwide. Exosomes delivery may play a key role in cross-talk among kidney cells and the progression of DN. However, the mechanisms underlying exosomes in DN remain unclear. METHODS: The cross-disciplinary study, including in vivo, in vitro, and human studies was conducted to explore the cross-talk between proximal tubular epithelial cells (PTECs) and mesangial cells (MCs) in DN. We purified exosome from PTECs treated with high glucose and db/db mice and assessed their influences in the pathologic change of MCs and downstream signal pathway. Healthy individuals and type 2 diabetic patients were enrolled to examine the role of exosomes in clinical applications. RESULTS: High glucose stimulated PTECs to secrete exosomal miR-92a-1-5p, which was taken-up by glomerular MCs, inducing myofibroblast transdifferentiation (MFT) in vitro and in vivo. PTEC-released exosomal 92a-1-5p decreased reticulocalbin-3 expression, leading to endoplasmic reticulum (ER) stress by downregulating genes essential for ER homeostasis including calreticulin and mesencephalic astrocyte-derived neurotrophic factor. Treatment with miR-92a-1-5p inhibitor ameliorated kidney damage in db/db mice with DN. Urinary miR-92a-1-5p could predict kidney injury in type 2 diabetic patients. CONCLUSIONS: PTEC-derived exosomal miR-92a-1-5p modulated the kidney microenvironment in vivo and in vitro models, which altered ER stress and MFT in MCs resulting in DN progression. Further blocking miR-92a-1-5p epigenetic regulatory network could be a potential therapeutic strategy to prevent the progression of DN. Video Abstract.