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1 Microvascular Research Laboratories, Department of Physiology, University of Bristol, Bristol, United Kingdom; Institute of Nephrology,First Teaching Hospital,, University of Beijing,3, Beijing, China
2 Microvascular Research Laboratories, Department of Physiology, University of Bristol, Bristol, United Kingdom
3 Children's Renal Unit, University of Bristol, Bristol, United Kingdom
4 Academic Renal Unit, University of Bristol, Bristol, United Kingdom
5 Bristol Urological Institute, Southmead Hospital, University of Bristol, Bristol, United Kingdom
6 Microvascular Research Laboratories, Department of Physiology, University of Bristol, Bristol, United Kingdom; Academic Renal Unit, University of Bristol, Bristol, United Kingdom
* To whom correspondence should be addressed. E-mail: Dave.Bates{at}bris.ac.uk.
Despite production by podocytes of the pro-angiogenic molecule Vascular Endothelial Growth Factor-A (VEGF) the glomeruli are not sites of angiogenesis. We recently described mRNA expression of an inhibitory splice variant of VEGF (VEGF165b) in normal kidney. Available anti-VEGF antibodies do not distinguish stimulatory from inhibitory VEGF families. To assess the production of VEGF165 (stimulatory) and VEGF165b (inhibitory) isoforms by human podocytes we examined both primary cultured and conditionally immortalised human podocytes using family and isoform specific RT-PCR. In addition, VEGF protein production was analysed in podocytes, using isoform specific double-stranded small-interference RNAs (siRNA). RT-PCR demonstrated the production of VEGF189 mRNA by podocytes of both phenotypes. In contrast, on differentiation there was a splicing change from VEGF165 to VEGF165b mRNA. In addition, VEGF protein in the supernatant of conditionally immortalised, differentiated podocytes was reduced by VEGF165b siRNA to 20 ± 11% of the level of mock-transfected cells, p<0.01. No reduction was seen with mismatch siRNA. Moreover, there was no reduction in VEGF protein concentration in the supernatant of primary cultured, de-differentiated human podocytes (109 ± 8% of mismatch siRNA, p>0.1). In conclusion, differentiated but not de-differentiated human podocytes secrete significant amounts of VEGF165b protein. It is possible that this may explain the paradox of high VEGF production in the glomerulus but no angiogenesis. Furthermore the existence of this splicing switch in relation to podocyte phenotype suggests that alternative splicing of the VEGF pre-RNA is a regulated process that is open to manipulation, and therefore could be a target for novel cancer therapies.
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