PKCδ regulates the stimulation of vascular endothelial factor mRNA translation by angiotensin II through hnRNP K

Kavithalakshmi Sataranatarajan, Myung Ja Lee, Meenalakshmi M. Mariappan, Denis Feliers

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Angiotensin II (Ang II)-induced renal injury is partly mediated by growth factors such as VEGF. We have previously shown that Ang II rapidly increases VEGF protein synthesis in proximal tubular epithelial (MCT) cells by augmenting mRNA translation, which is partly dependent on activation and binding of hnRNP K to 3′ untranslated region (UTR) of VEGF mRNA. Regulation of hnRNP K activation by PKCδ was studied in MCT cells. Transfection with a PKCδ siRNA inhibited hnRNP K Ser302 phosphorylation and activation, and reduced Ang II stimulation of VEGF synthesis. Inhibition of PKCδ with röttlerin also prevented binding of hnRNP K to VEGF mRNA and reduced the efficiency of VEGF mRNA translation. In db/db mice at 2 weeks of type 2 diabetes, VEGF expression was increased, which was due not to increase in transcription but to augmented translation of VEGF mRNA. Augmented VEGF expression was associated with increased binding of hnRNP K to VEGF mRNA. c-src and PKCδ activities and hnRNP K phosphorylation on Ser302 in renal cortex of db/db mice were increased compared to control mice. We conclude: Ang II-induced VEGF mRNA translation is associated with activation of hnRNP K in MCT cells. In the signaling pathway leading to hnRNP K activation induced by Ang II, PKCδ is downstream of c-src. PKCδ-mediated phosphorylation of hnRNP K is required for Ang II stimulation of VEGF mRNA translation. In mice with type 2 diabetes, src and PKCδ activation and hnRNP K phosphorylation correlate with increased VEGF mRNA translation and kidney hypertrophy. 3′ UTR events are important in regulation of VEGF expression in models of renal injury.

Original languageEnglish (US)
Pages (from-to)969-977
Number of pages9
JournalCellular Signalling
Volume20
Issue number5
DOIs
StatePublished - May 1 2008

Keywords

  • Angiotensin II
  • Serine phosphorylation
  • Signal transduction
  • Tyrosine phosphorylation
  • VEGF
  • mRNA translation
  • src, PKCδ

ASJC Scopus subject areas

  • Cell Biology

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