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Am J Physiol Renal Physiol (August 31, 2004). doi:10.1152/ajprenal.00146.2004
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Submitted on April 22, 2004
Accepted on August 18, 2004

Vascular endothelial growth factor and nephrin interact and reduce apoptosis in human podocytes

Rebecca R. Foster1, Moin A. Saleem2, Peter W. Mathieson3, David O. Bates1*, and Steven J. Harper1

1 Department of Physiology, University of Bristol, Microvascular Research Laboratories, Bristol, United Kingdom
2 University of Bristol, Children's Renal Unit, Bristol, United Kingdom
3 University of Bristol, Academic Renal Unit, Bristol, United Kingdom

* To whom correspondence should be addressed. E-mail: Dave.Bates{at}bris.ac.uk.

VEGF is anti-cytotoxic in podocytes. Moreover, it has been suggested that nephrin, a cell adhesion molecule of the podocyte slit diaphragm can contribute to anti-apoptotic mechanisms in these cells. We therefore investigated whether VEGF signals to reduce apoptosis, and the role of nephrin in this survival mechanism. Flow cytometry showed that human cells with nephrin mutations had significantly greater proportion of apoptosis. Although VEGF reduced apoptosis in human conditionally immortalised podocytes (wild type, WTs) by 18.1% of control (p<0.001), it was unable to do so in nephrin deficient human conditionally immortalised podocytes (NDs). Moreover, Western blotting and immunodetection with an anti-nephrin antibody showed that the phosphorylation of nephrin, compared to serum starved WTs, was significantly increased (ratio of 3.36±1.2 to control, p<0.05) by VEGF treatment and significantly reduced by treatment with a neutralising VEGF monoclonal antibody (Mab) (ratio of 0.2±0.09 to control, p<0.05). The AKT signalling pathway has been implicated in nephrin-mediated inhibition of apoptosis in transfected cells, but the role of this pathway has not previously been shown in podocytes. Surprisingly, exogenous VEGF decreased AKT/PKB phosphorylation in normal podocytes but increased it in nephrin deficient podocytes. We suggest therefore that both exogenous and endogenous (podocyte derived) VEGF can stimulate the phosphorylation of nephrin and through this action may prevent podocyte apoptosis. However, the involvement of AKT in this survival response in normal human podocytes is not clear.




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