Abstract
Podocytes are terminally differentiated cells with little proliferative capacity. The high expression levels of cell cycle inhibitory proteins, including p21, p27, and p57, play an important role in maintaining the low level of proliferation of mature podocytes. In the present study, we aimed to explore the role of yes-associated protein (YAP) signalling in adriamycin-induced podocyte re-entry into the cell cycle and dedifferentiation. Proliferating cell nuclear antigen (PCNA)-, cyclin-dependent kinase 4 (CDK4)-, and Cyclin D1-positive podocytes were found in mice with adriamycin-induced nephropathy. In vitro, adriamycin administration increased the percentage of cells in S phase and the upregulation of mesenchymal-related marker proteins. CDK4 and cyclin D1 were significantly up-regulated after incubation with adriamycin. Overexpression of YAP in podocytes promoted their entry into the cell cycle; up-regulated cyclin D1, desmin, and snail2 expression and down-regulated Wilms’ tumour 1 (WT1) and nephrin production. Recombinant murine FGF-basic induced podocytes to re-enter the cell cycle, inhibited WT1 and nephrin, and increased desmin and snail2 expression. Pretreating podocytes with verteporfin, an inhibitor of YAP/ TEA domain transcription factor (TEAD), decreased the adriamycin-induced overexpression of cyclin D1 and reduced the ratio of S-phase podocytes. This result was further verified by knocking down YAP expression using RNA interference. In conclusion, adriamycin induced podocytes to re-enter the cell cycle via upregulation of CDK4 and cyclin D1 expression, which was at least partly mediated by YAP signalling. Re-entry into the cell cycle induced the over-expression of mesenchymal markers in podocytes.
Highlights
Proteinuria is the main clinical manifestation of kidney disease and podocyte injury is the cytological basis for the development of large amounts of proteinuria[1]
The present study showed that adriamycin promoted the re-entry of mature podocytes into the cell cycle by upregulating the expression of cyclin D1 and cyclin-dependent kinase 4 (CDK4), whereas cell cycle-associated protein inhibitors were not involved in this process
yes-associated protein (YAP) played an important role in this process, since it promoted podocyte cell cycle re-entry by up-regulating the expression of cyclin D1, desmin, and snail[2] proteins, promoting the dedifferentiation of podocytes
Summary
Proteinuria is the main clinical manifestation of kidney disease and podocyte injury is the cytological basis for the development of large amounts of proteinuria[1]. Known as glomerular visceral epithelial cells, are terminally differentiated cells with little or no proliferative capacity They cover the glomerular basement membrane and their adjacent foot processes are staggered, forming a Escape from the cell cycle due to the high expression levels of cell cycle inhibitory proteins, including p21, p27, and p57, is the main reason mature podocytes can maintain low levels of proliferation[4]. C In vitro experiments showed the expression of PCNA in podocytes after adriamycin (0.25 μg/mL) treatment for the indicated time (magnification, ×200). I Western blotting analysis of the expression of cell cycleassociated proteins and their inhibitors in podocytes treated with adriamycin (0.25 μg/mL) for the indicated time periods. K Immunohistochemical analysis showed that CDK4 and cyclin D1 were expressed in podocytes of adriamycin-treated mice; the arrow indicates the location of the podocyte and the magnification was ×400. CON control, ADR Adriamycin, DAPI 4′,6-diamidino-2-phenylindole. *P < 0.05 vs. control group
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