Submitted on May 17, 2009
Revised on September 25, 2009
Accepted on October 14, 2009
The balance of autocrine VEGF-A and VEGF-C determines podocyte survival
Janina Mueller-Deile1, Kirstin Worthmann1, Moin A Saleem2, Irini Tossidou3, Hermann Haller3, and Mario Schiffer1*
1 Hannover Medical School
2 University of Bristol, Southmead Hospital
3 Medical School Nephrology
* To whom correspondence should be addressed. E-mail: schiffer.mario{at}mh-hannover.de.
Podocytes are an important component of the glomerular filtration barrier and are the major source of vascular endothelial growth factor (VEGF) in the glomerulus. The role of VEGF for the phenotype of the glomerular endothelium has been intensely studied, however the direct effects of autocrine VEGF on the podocyte are largely unknown. In this study we characterized the expression of VEGF isoforms and VEGF receptors in cultured human podocytes and examined direct effects on cell signaling and apoptosis after stimulation with exogenous VEGF or ablation of autocrine VEGF. We identified VEGF-A and VEGF-C as the dominant isoforms in human podocytes and showed that autocrine levels of both are important for the intracellular activation of anti-apoptotic PI3K/AKT, and suppression of the pro-apoptotic p38MAPK via VEGFR-2. We demonstrated that ablation of VEGF-A or VEGF-C as well as treatment with bevacizumab or a VEGFR-2/-3-tyrosine-kinase-inhibitor led to reduced podocyte survival. In contrast, ablation of VEGF-B had no effect on podocyte survival. Treatment with exogenous VEGF-C reversed the effect of VEGF-A neutralization and exogenous VEGF-A abrogated the effect of VEGF-C ablation in human podocytes. Our results underline the importance of autocrine VEGF for podocyte survival and indicate the delicate balance of VEGF-A and VEGF-C to influence progression of glomerular diseases.
