NDT Advance Access originally published online on March 14, 2008
Nephrology Dialysis Transplantation 2008 23(7):2179-2191; doi:10.1093/ndt/gfn085
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Advanced glycation end-products induce cell cycle arrest and hypertrophy in podocytes
1 Klinik für Innere Medizin III 2 Klinik für Innere Medizin I, Friedrich-Schiller-University, Jena, Germany
Correspondence and offprint requests to: Gunter Wolf, Klinik für Innere Medizin III, Friedrich-Schiller-University, Erlanger-Allee 101, D-07740 Jena, Germany. Tel: +49-3641-9324301; Fax: +49-3641-9324302; E-mail: gunter.wolf{at}med.uni-jena.de
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Abstract |
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Background. Podocyte injury with loss of cells into the urine seems to be an early factor in diabetic nephropathy. Advanced glycation end-products (AGEs) are important mediators of structural and functional renal abnormalities in diabetic nephropathy. We and others have previously described that mice with a deletion in the gene for the cell cycle regulatory p27Kip1 are protected from some features of diabetic nephropathy.
Methods. The present study investigates a potential influence of AGE-modified bovine serum albumin (AGE-BSA) on podocyte growth and p27Kip1 expression in culture. The p27Kip1 expression was measured by western blots and real-time PCR. Cell cycle analysis, cell hypertrophy, proliferation and various markers of apoptosis and necrosis were assessed. The p27Kip expression was inhibited by siRNA or was overexpressed in podocytes with an inducible expression system.
Results. AGE-BSA was actively taken up into the cell as determined by immunohistochemistry, western blots and HPLC. Incubation with AGE-BSA induced in differentiated podocytes, but not in tubular cells, p27Kip1 mRNA and protein expression. This induction was associated with cell cycle arrest of podocytes, cell hypertrophy (as measured by increases in cell size and protein/cell number ratios) and an increase in necrotic, but not apoptotic cells. Inhibition of p27Kip1 expression with siRNA halted the AGE-BSA-mediated cell cycle arrest and hypertrophy, but did not interfere with AGE uptake into podocytes. In contrast, overexpression of p27Kip1 using an inducible expression system stimulated hypertrophy and cell cycle arrest of podocytes.
Conclusion. Our data demonstrate that AGE-BSA-induced hypertrophy and damage of cultured podocytes occurs by a mechanism involving p27Kip1. This effect can contribute to the loss of podocytes in diabetic nephropathy.
Keywords: advanced glycation end-products (AGEs); cell cycle regulation; diabetic nephropathy; podocytes
Received for publication: 29. 8.07
Accepted in revised form: 29. 1.08
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