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Am J Physiol Renal Physiol (June 8, 2004). doi:10.1152/ajprenal.00040.2004
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Submitted on February 5, 2004
Accepted on June 1, 2004

Differential regulation of VEGF by TGF-{beta} and hypoxia in rat proximal tubular cells

Takahiko Nakagawa1*, Hui Y. Lan2, Hong J. Zhu3, Duk-Hee Kang4, George F. Schreiner5, and Richard J. Johnson1

1 Division of Nephrology, Hypertension and Transplantation, University of Florida, Gainesville, FL, USA; Division of Nephrology-Medicine, Baylor College of Medicine, Houston, TX, USA
2 Division of Nephrology-Medicine, Baylor College of Medicine, Houston, TX, USA
3 Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Victoria, Australia
4 Division of Nephrology, Ewha women's University Hospital, Seoul, Korea, Republic of
5 Scios Inc., Sunnyvale, CA, USA

* To whom correspondence should be addressed. E-mail: nakagt{at}medicine.ufl.edu.

Abstract 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 TGF-{beta} dependent fibrosis, both of which are known to stimulate VEGF. Since the TGF-{beta}/Smad pathway is activated in hypoxia, we tested the hypothesis that the induction of VEGF in hypoxia could be partially dependent on TGF-{beta}. Rat proximal tubular (NRK52E) cells treated with TGF-{beta} under normoxic conditions secreted VEGF at 24 hours, 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-{beta}. However, the induction of VEGF occurs prior to synthesis of TGF-{beta} and is not blocked by either a TGF-{beta} antagonist, by Smad7 overexpression, or by blocking ERK1/2, whereas induction is blocked by PKC inhibition or partially by p38 inhibitor. Finally, the addition of TGF-{beta} with hypoxia results in significantly more VEGF expression than either stimulation alone. Thus, TGF-{beta} and hypoxia act via additive/synergistic but distinct pathways to stimulate VEGF in proximal tubular cells, a finding which may be important as to how VEGF is stimulated in renal disease.




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