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 β-catenin nuclear accumulation. Moreover, we regulated the expression of β-catenin and demonstrated that miR-221 in EVs mediated proximal tubule cells injury through Wnt/β-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.

足细胞损伤是糖尿病性肾病（DN）引发的关键事件。肾小管间质，特别是近端小管已被认为是损伤的目标。在本研究中，我们表明足细胞在高糖条件下诱导近端肾小管上皮细胞（PTEC）的去分化，而细胞外囊泡（EVs）介导了相互作用。然后，我们提取并鉴定了这些源自足细胞的EV作为外来体，此外，这些EV诱导了PTEC的去分化。提取足细胞来源的电动汽车的总microRNA（miRNA）表达，并显着增加miR-221表达。通过利用miRNA功能获得和丧失的方法，我们观察到miR-221介导的PTEC去分化。此外，双重萤光素酶报告基因检测证实miR-221直接靶向DKK2，它是Wnt信号的抑制剂，miR-221的过表达显着导致β-catenin核积累。此外，我们调节了β-catenin的表达并证明了EV中的miR-221通过Wnt /β-catenin信号传导介导了近端小管细胞的损伤。此外，对糖尿病小鼠中miR-221的抑制逆转了PTECs去分化相关蛋白的异常表达。这些发现为糖尿病肾病中近端小管细胞损伤的机制提供了独特的见解。糖尿病小鼠中miR-221的抑制逆转了PTECs去分化相关蛋白的异常表达。这些发现为糖尿病肾病中近端小管细胞损伤的机制提供了独特的见解。糖尿病小鼠中miR-221的抑制逆转了PTECs去分化相关蛋白的异常表达。这些发现为糖尿病肾病中近端小管细胞损伤的机制提供了独特的见解。