Exosomes from high glucose-treated glomerular endothelial cells trigger the epithelial-mesenchymal transition and dysfunction of podocytes

Abstract

New data indicate that abnormal glomerular endothelial cell (GEC)-podocyte crosstalk plays a critical role in diabetic nephropathy (DN). The aim of our study is to investigate the role of exosomes from high glucose (HG)-treated GECs in the epithelial-mesenchymal transition (EMT) and dysfunction of podocytes. In this study, exosomes were extracted from GEC culture supernatants and podocytes were incubated with the GEC-derived exosomes. Here, we demonstrate that HG induces the endothelial-mesenchymal transition (EndoMT) of GECs and HG-treated cells undergoing the EndoMT secrete more exosomes than normal glucose (NG)-treated GECs. We show that GEC-derived exosomes can be internalized by podocytes and exosomes from HG-treated cells undergoing an EndoMT-like process can trigger the podocyte EMT and barrier dysfunction. Our study reveals that TGF-β1 mRNA is enriched in exosomes from HG-treated GECs and probably mediates the EMT and dysfunction of podocytes. In addition, our experimental results illustrate that canonical Wnt/β-catenin signaling is involved in the exosome-induced podocyte EMT. Our findings suggest the importance of paracrine communication via exosomes between cells undergoing the EndoMT and podocytes for renal fibrosis in DN. Thus, protecting GECs from the EndoMT and inhibiting TGF-β1-containing exosomes release from GECs is necessary to manage renal fibrosis in DN.

Exosomal miRNA-215-5p Derived from Adipose-Derived Stem Cells Attenuates Epithelial–Mesenchymal Transition of Podocytes by Inhibiting ZEB2

“…Exosomes are the nanosized membrane-bound delivery vesicles, which play a critical role in regulating cellular biofunction by mediating cell-to-cell communication [31]. Exosomes extracted from HG-treated glomerular endothelial cells (GECs) can be internalized by podocytes, leading to podocyte EMT and renal fibrosis [32,33]. In contrast, some exosomes exert protective effects to be used for treatment of many diseases including podocyte injury and kidney disease.…”

Extracellular Vesicles as Signaling Mediators and Disease Biomarkers across Biological Barriers

“…Furthermore, the podocytes, which reside in the visceral layer of Bowman's capsule and form the final filtration barrier, are connected to the GBM by interdigitated foot processes that leave open only thin gaps, designated filtration slits, for filtration through the GBM. These slits, however, are coated by a diaphragm of filter proteins, such as podocin, nephrins, podocalyxin, and protocadherins, which further reduce the filtration surface [250,252]. Thus, glomerular filtration is highly selective: only molecular complexes below 6.4 nm in diameter and under 70 kDa may physiologically transit into the lumen of the nephron [253].…”

“…These endothelial EVs may vehiculate TGF-β1 mRNA, a key mediator of the epithelial-mesenchymal transition, whose translation activates myofibroblastic intracapsular proliferation and glomerular dysfunction. Thus, an EV-mediated endothelial-podocyte crosstalk contributes to glomerular fibrosis and loss of renal function in diabetic nephropathy [252].…”

Roles for Exosome in Various Kidney Diseases and Disorders

“…Exosomes isolated from high-glucose-treated glomerular endothelial cells played a crosstalk role to activate EMT and fibrotic changes of mesangial cells and podocytes in DN. Wu et al, 2017) (Continued)…”

“…A recent study has shown that type 1 DN was associated with increases in urinary excretion of exosomal plasmin, prostasin, and urokinase as well as the proteolytic activation of ENaC that might contribute to the dysfunction of Na + excretion and hypertension (Andersen et al, 2015). Interestingly, exosomes derived from high-glucose-treated glomerular endothelial cells played a crosstalk role to activate epithelial mesenchymal transition (EMT) and fibrotic changes of glomerular mesangial cells and podocytes in DN Wu et al, 2017). High-glucose also enhanced secretion of exosomes from macrophages, which then caused mesangial proliferation and activated inflammatory cascade in the renal tissue (Zhu et al, 2019b).…”