Podocyte-derived extracellular vesicles mediate renal proximal tubule cells dedifferentiation via microRNA-221 in diabetic nephropathy.

ABSTRACT

Podocyte injury is a key event in the initiation of Diabetic nephropathy (DN). Tubulointerstitium, especially the proximal tubule has been regarded as a target of injury. In the present study, we showed that podocytes induced dedifferentiation of proximal tubular epithelial cells(PTECs) in high-glucose conditions and extracellular vesicles (EVs) mediates the interaction. Then we extracted and identified these EVs derived from podocytes as exosome, further, the EVs induced PTECs dedifferentiation. Total microRNA(miRNA) expression of podocyte-derived EVs was extracted and miR-221 expression was remarkably increased. By making use of the miRNA gain- and loss-of-function approaches, we observed that miR-221 mediated PTECs dedifferentiation. In addition, a dual-luciferase reporter assay confirmed that miR-221 direct target DKK2, which was an inhibitor of Wnt signaling, and overexpression of miR-221 significantly resulted in ß-catenin nuclear accumulation. Moreover, we regulated the expression of ß-catenin and demonstrated that miR-221 in EVs mediated proximal tubule cells injury through Wnt/ß-catenin signaling. Furthermore, inhibition of miR-221 in diabetic mice reversed the abnormal expression of PTECs dedifferentiation related protein. These findings provide unique insights in the mechanisms of proximal tubule cell injury in diabetic nephropathy.