Differential regulation of VEGF by TGF-β and hypoxia in rat proximal tubular cells

Takahiko Nakagawa, Hui Y. Lan, Hong J. Zhu, Duk Hee Kang, George F. Schreiner, Richard J. Johnson

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57 Scopus citations


VEGF expression by proximal tubular epithelial cells may play a critical role in maintaining peritubular capillary endothelium in renal disease. Two major processes involved in renal injury include hypoxia (from vasoconstriction or vascular injury) and transforming growth factor (TGF)-β-dependent fibrosis, both of which are known to stimulate VEGF. Because the TGF-β/Smad pathway is activated in hypoxia, we tested the hypothesis that the induction of VEGF in hypoxia could be partially dependent on TGF-β. Rat proximal tubular (NRK52E) cells treated with TGF-β under normoxic conditions secreted VEGF at 24 h, and this was significantly reduced by blocking Smad activation by overexpressing the inhibitory Smad7 or by blocking p38 and ERK1/2 MAP kinase activation or protein kinase C activation with specific inhibitors. With acute hypoxia, rat proximal tubular cells also express VEGF mRNA and protein as well as TGF-β. However, the induction of VEGF occurs before synthesis of TGF-β and is not blocked by either a TGF-β antagonist, by Smad7 overexpression, or by blockage of ERK1/2, whereas induction is blocked by PKC inhibition or partially blocked by a p38 inhibitor. Finally, the addition of TGF-β with hypoxia results in significantly more VEGF expression than either stimulation alone. Thus TGF-β and hypoxia act via additive/synergistic but distinct pathways to stimulate VEGF in proximal tubular cells, a finding that may be important in understanding how VEGF is stimulated in renal disease.

Original languageEnglish
Pages (from-to)F658-F664
JournalAmerican Journal of Physiology - Renal Physiology
Issue number4 56-4
StatePublished - Oct 2004


  • Angiogenesis
  • Mitogen-activated protein kinase
  • Protein kinase C
  • Renal
  • Smad
  • Transforming growth factor-β
  • Vascular endothelial growth factor


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