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Heterogeneous nuclear ribonucleoprotein K contributes to angiotensin II stimulation of vascular endothelial growth factor mRNA translation

¹O'Brien Kidney Research Center, Department of Medicine/Nephrology, University of Texas Health Science Center, and ²South Texas Veterans Health Care System, San Antonio, Texas; and ³University of Washington Medicine Lake Union, University of Washington, Seattle, Washington

Submitted 14 December 2006 ; accepted in final form 8 June 2007

ANG II rapidly increases VEGF synthesis in proximal tubular epithelial cells through mRNA translation. The role of heterogeneous nuclear ribonucleoprotein K (hnRNP K) in ANG II regulation of VEGF mRNA translation initiation was examined. ANG II activated hnRNP K as judged by binding to poly(C)- and poly(U)-agarose. ANG II increased hnRNP K binding to VEGF mRNA at the same time as it stimulated its translation, suggesting that hnRNP K contributes to VEGF mRNA translation. Inhibition of hnRNP K expression by RNA interference significantly reduced ANG II stimulation of VEGF synthesis. ANG II increased hnRNP K phosphorylation on both tyrosine and serine residues with distinct time courses; only Ser302 phosphorylation paralleled binding to VEGF mRNA. Src inhibition using PP2 or RNA interference inhibited PKC activity and prevented hnRNP K phosphorylation on both tyrosine and serine residues and its binding to VEGF mRNA. Under these conditions, ANG II-induced VEGF synthesis was inhibited. ANG II treatment induced redistribution of both VEGF mRNA and hnRNP K protein from light to heavy polysomal fractions, suggesting increased binding of hnRNP K to VEGF mRNA that is targeted for increased translation. This study shows that hnRNP K augments efficiency of VEGF mRNA translation stimulated by ANG II.

ANG II; VEGF; signal transduction; RNA-binding protein

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