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1 Pediatrics/Nephrology, Albert Einstein College of Medicine, Bronx, New York, United States; Developmental and Molecular Biology, Albert Einstein College of Medicine, New York
2 Pediatrics/Nephrology, Albert Einstein College of Medicine, Bronx, New York, United States; Developmental and Molecular Biology, Albert Einstein College of Medicine
3 Medicine, Mount Sinai School of Medicine, New York, New York, United States
* To whom correspondence should be addressed. E-mail: atufro{at}aecom.yu.edu.
Vascular endothelial growth factor (VEGF-A) signaling is required for endothelial cell differentiation, vasculogenesis, angiogenesis and vascular patterning. During kidney morphogenesis, podocyte VEGF-A guides endothelial cells towards developing glomeruli. Podocyte VEGF-A expression continues throughout life but its function after completion of development remains unclear. Here we examined the expression of VEGF-A and its receptors VEGFR1, VEGFR2, NP1 and NP2 in conditionally immortalized mouse podocytes cultured in undifferentiated and differentiated conditions using RT-PCR and western analysis. VEGF-A secretion was assessed by ELISA and western analysis. Upon podocyte differentiation VEGF-A protein expression and secretion increased three- fold. Differentiated podocytes expressed eight-fold higher VEGFR2 mRNA levels than undifferentiated podocytes, whereas VEGFR1, sVEGFR1, NP1 and NP2 mRNA levels were similar. We examined the regulation and function of the VEGF-A system by exposing differentiated podocytes to recombinant VEGF165 [20ng/ml] or control media for 24h. VEGF165 induced a two-fold increase in VEGFR2 mRNA and protein levels whereas VEGFR1, sVEGFR1, NP1 and NP2 mRNA levels remained unchanged. VEGF165 induced VEGFR2 phosphorylation. VEGF165 reduced podocyte apoptosis ~40% whereas anti-VEGFR2 neutralizing antibody enhanced it two-fold. We determined that VEGF-A signaling regulates slit diaphragm proteins by inducing a dose-response podocin upregulation and increasing its interaction with CD2AP. The data indicate that podocytes in culture have a functional autocrine VEGF-A system that is regulated by differentiation and ligand availability. VEGF-A functions in podocytes include promoting survival through VEGFR2, inducing podocin upregulation and increasing podocin/CD2AP interaction.
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