Abstract
Diabetic kidney disease (DKD) is a serious and common complication of diabetes. Extracellular vesicles (EVs) have emerged as crucial vectors in cell-to-cell communication during the development of DKD. EVs may mediate intercellular communication between podocytes and proximal tubules. In this study, EVs were isolated from podocyte culture supernatants under high glucose (HG), normal glucose (NG), and iso-osmolality conditions, and then co-cultured with proximal tubular epithelial cells (PTECs). MicroRNAs (miRNA) sequencing was conducted to identify differentially expressed miRNAs of podocyte EVs and bioinformatics analysis was performed to explore their potential functions. The results showed that EVs secreted from HG-treated podocytes induced apoptosis of PTECs. Moreover, five differentially expressed miRNAs in response to HG condition were identified. Functional enrichment analysis revealed that these five miRNAs are likely involved in biological processes and pathways related to the pathogenesis of DKD. Overall, these findings demonstrate the pro-apoptotic effects of EVs from HG-treated podocytes on PTECs and provide new insights into the pathologic mechanisms underlying DKD.
Highlights
Diabetic kidney disease (DKD) is a serious and common microvascular complication of diabetes mellitus (DM) and a primary cause of end-stage renal disease (ESRD; Tuttle et al, 2014)
Extracellular vesicles (EVs) were extracted from the cell culture supernatants of approximately 3.6 × 106 podocytes that treated with normal glucose (NG), MA, and high glucose (HG) stimulation
The percentage of TUNEL positive proximal tubular epithelial cells (PTECs) were higher in HG-podo-EVs group as compared to other groups (Figure 3D). These findings indicate that EVs from HG-treated podocytes exert a pro-apoptotic effect in PTECs cultured under NG or HG conditions
Summary
Diabetic kidney disease (DKD) is a serious and common microvascular complication of diabetes mellitus (DM) and a primary cause of end-stage renal disease (ESRD; Tuttle et al, 2014). The dysfunction and depletion of podocytes causes proteinuria (Mundel and Shankland, 2002), which is an intensive instigator of tubulointerstitial inflammation and fibrosis (Wang et al, 2000; Abbate et al, 2006; Gorriz and Martinez-Castelao, 2012). Filtered proteins induce the production of cytokines and chemokines by proximal tubular epithelial cells (PTECs), which subsequently leads to the infiltration of inflammatory cells and, to tubulointerstitial fibrogenesis and progression to ESRD. Kidney biopsies of some DKD patients with normal albuminuria/ microalbuminuria, but elevated serum creatinine, revealed severe tubular interstitial lesions with mild glomerular lesions. Apart from proteinuria, there may exist other mechanisms that mediate the crosstalk between podocytes and the proximal tubules
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