Selective down‐regulation of anti‐angiogenic splice variants of VEGF by IGF‐1 is mediated by PKC, PI‐3K and SRPK1/2

VEGF, the predominant regulatory molecule in angiogenesis, is differentially spliced in its terminal exon (exon 8) to produce either pro‐angiogenic VEGF xxx or anti‐angiogenic VEGF xxx b isoforms. We have shown that IGF‐1 specifically down‐regulates VEGF xxx b expression in proliferating podocytes. Here, we investigated the role of PKC and PI‐3K in IGF‐1‐dependent down‐regulation of VEGF xxx b expression after 48 hours of treatment. VEGF xxx b proteins were measured in cell lysates by isoform‐specific ELISA. VEGF xxx b expression was decreased by IGF‐1 (0.28±0.05 fold to control). BIMI, an inhibitor of PKC kinases, prevented IGF‐1 down‐regulation of VEGF xxx b expression (1.14±0.04 fold to control). SRPIN340, an inhibitor of SRPK1/2 (serine‐arginine (SR) Protein Kinase 1 and 2) kinases implicated in splicing control by phosphorylating splicing factors, inhibited IGF‐1 down‐regulation of VEGF xxx b expression (1.17±0.14 fold). These results indicate that IGF‐1 decreases the synthesis of VEGF xxx b isoforms in proliferating podocytes through PKC, PI‐3K and SRPK1/2 kinases. Funded by the BHF (FS04/09, and BS06/005).