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Am J Physiol Renal Physiol (March 4, 2003). doi:10.1152/ajprenal.00276.2002
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Submitted on August 2, 2002
Accepted on February 22, 2003

FUNCTIONAL EVIDENCE THAT VASCULAR ENDOTHELIAL GROWTH FACTOR MAY ACT AS AN AUTOCRINE FACTOR ON HUMAN PODOCYTES

Rebecca R. Foster1, Rachel Hole2, Karen Anderson3, Simon C. Satchell3, Richard J. Coward4, Peter W. Mathieson3, David A. Gillatt5, Moin A. Saleem4, David O. Bates1*, and Steven J. Harper6

1 Department of Physiology, Microvascular Research Laboratories, University of Bristol, Bristol, England, United Kingdom
2 Department of Pathology, Southmead Hospital, Bristol, England, United Kingdom
3 Academic Renal Unit, Southmead Hospital, University of Bristol, Bristol, England, United Kingdom
4 Children's Renal Unit, Southmead Hospital, University of Bristol, Bristol, England, United Kingdom
5 Southmead Hospital, University of Bristol, Bristol Urology Institute, Bristol, England, United Kingdom
6 Department of Physiology, Microvascular Research Laboratories, University of Bristol, Bristol, England, United Kingdom; Academic Renal Unit, Southmead Hospital, University of Bristol, Bristol, England, United Kingdom

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

Vascular Endothelial Growth factor (VEGF) is expressed by renal glomerular epithelial cells (podocytes), and is thought to be protective against nephrotoxic agents. VEGF has been shown to be an autocrine survival factor in neuropilin-1 positive, VEGF receptor negative, breast carcinoma cells. Normal human podocytes are also known to express neuropilin-1, VEGF and are VEGF-R2 negative. Here we have investigated whether a similar VEGF autocrine loop may exist in podocytes. Podocyte cytosolic calcium concentration ([Ca2+]i) was analysed in primary cultured and conditionally immortalised podocytes using ratiometric fluorescence measurement (R). Cytotoxicity was determined by LDH assay, proliferation by 3H-thymidine incorporation and cell counts by haemocytometric assay. VEGF decreased ([Ca2+]i) in primary podocytes (from 179±36nM to 121±25nM, p< 0.05) and conditionally immortalised podocytes (from 95±10nM to 66±8nM, p<0.02) in the absence of extracellular calcium. The type III receptor tyrosine-kinase inhibitor PTK787/ZK222584 abolished this reduction. VEGF increased podocyte 3H-thymidine incorporation (3349±283cpm, control 2364±301cpm, p<0.05) and cell number (4.5±0.7 x 104/ml, control 2.6±0.5x 104/ml, p<0.05) and decreased cytotoxicity (5.9±0.7%, control 12±3%, p<0.05), whereas a monoclonal antibody to VEGF increased cytotoxicity. Electron microscopy on normal human glomeruli demonstrated that the glomerular VEGF is mostly podocyte cell membrane associated. These results indicate that one of the functions of VEGF secreted from podocytes may be to act as an autocrine factor on calcium homeostasis and cell survival.




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