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

Vascular endothelial growth factor (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 antiapoptotic mechanisms in these cells. We therefore investigated whether VEGF signals to reduce apoptos...

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Published in:American journal of physiology. Renal physiology 2005-01, Vol.288 (1), p.F48-F57
Main Authors: Foster, Rebecca R, Saleem, Moin A, Mathieson, Peter W, Bates, David O, Harper, Steven J
Format: Article
Language:English
Subjects:
Apoptosis - drug effects
Apoptosis - physiology
Cell Line
Gene Components
Humans
Kidney Glomerulus - cytology
Kidney Glomerulus - physiology
Membrane Proteins
Mutation
Phosphorylation
Protein Conformation
Protein Structure, Tertiary
Protein-Serine-Threonine Kinases - metabolism
Proteins - genetics
Proteins - physiology
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-akt
Vascular Endothelial Growth Factor A - physiology
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Summary:Vascular endothelial growth factor (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 antiapoptotic 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 podocytes with nephrin mutations had a significantly greater proportion of apoptosis. Although VEGF reduced apoptosis in human conditionally immortalized podocytes [wild-type (WT)] by 18.1% of control (P < 0.001), it was unable to do so in nephrin-deficient human conditionally immortalized podocytes. Moreover, Western blotting and immunodetection with an anti-nephrin antibody showed that the phosphorylation of nephrin, compared with 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 neutralizing VEGF monoclonal antibody (mAb) (ratio of 0.2 +/- 0.09 to control, P < 0.05). The AKT signaling 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.
ISSN:1931-857X
1522-1466
DOI:10.1152/ajprenal.00146.2004