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      Transforming Growth Factor-β 1 Induces Vascular Endothelial Growth Factor Expression in Murine Proximal Tubular Epithelial Cells

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          Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen that promotes angiogenesis, vasculogenesis, and increases vascular permeability. VEGF is expressed in renal tubular epithelial cells and urinary VEGF excretion is increased in various glomerular disorders. However, the mechanisms underlying expression of VEGF in renal tubular epithelial cells have not been fully elucidated. In the present study, we attempted to define a predominant regulator of VEGF expression using a cultured murine renal proximal tubular epithelial cell line (mProx24). VEGF protein concentration in the culture supernatant was measured by sandwich enzyme-linked immunosorbent assay. mProx24 constitutively produced VEGF at low level. Major isoforms expressed in this cell line were VEGF<sub>164</sub> and VEGF<sub>120</sub> determined by reverse transcription-polymerase chain reaction method. Among various stimuli including angiotensin II, transforming growth factor-β<sub>1</sub> (TGF-β<sub>1</sub>), lipopolysaccharides, interleukin-1β, interleukin-10 and interferon-γ, only TGF-β<sub>1</sub> significantly increased the level of VEGF protein at 24 h in a dose-dependent manner. The steady-state mRNA level of VEGF was dose dependently increased by TGF-β<sub>1</sub> detected by Northern blotting. Treatment with neutralizing anti-TGF-β<sub>1</sub> antibody abolished TGF-β<sub>1</sub>-induced VEGF expression by 70%. Inhibitors of protein kinase C (PKC), Ro-31-8220 and staurosporin, significantly suppressed TGF-β<sub>1</sub>-induced VEGF protein expression. These results demonstrate the role of TGF-β<sub>1</sub> on the expression of VEGF in proximal tubular epithelial cells mediated potentially via PKC pathway. This regulatory mechanism may be associated with the progression of tubulointerstitial lesions in renal disorders.

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          Most cited references 5

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          Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1.

          Angiopoietin-1 (Ang1) and vascular endothelial growth factor (VEGF) are endothelial cell-specific growth factors. Direct comparison of transgenic mice overexpressing these factors in the skin revealed that the VEGF-induced blood vessels were leaky, whereas those induced by Ang1 were nonleaky. Moreover, vessels in Ang1-overexpressing mice were resistant to leaks caused by inflammatory agents. Coexpression of Ang1 and VEGF had an additive effect on angiogenesis but resulted in leakage-resistant vessels typical of Ang1. Ang1 therefore may be useful for reducing microvascular leakage in diseases in which the leakage results from chronic inflammation or elevated VEGF and, in combination with VEGF, for promoting growth of nonleaky vessels.
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            Vascular endothelial growth factor is essential for corpus luteum angiogenesis.

            The development and endocrine function of the ovarian corpus luteum (CL) are dependent on the growth of new capillary vessels. Although several molecules have been implicated as mediators of CL angiogenesis, at present there is no direct evidence for the involvement of any. Here we report the unexpected finding that treatment with truncated soluble Flt-1 receptors, which inhibit vascular endothelial growth factor (VEGF) bioactivity, resulted in virtually complete suppression of CL angiogenesis in a rat model of hormonally induced ovulation. This effect was associated with inhibition of CL development and progesterone release. Failure of maturation of the endometrium was also observed. Areas of ischemic necrosis were demonstrated in the corpora lutea (CLs) of treated animals. However, no effect on the preexisting ovarian vasculature was observed. These findings demonstrate that, in spite of the redundancy of potential mediators, VEGF is essential for CL angiogenesis. Furthermore, they have implications for the control of fertility and the treatment of ovarian disorders characterized by hypervascularity and hyperplasia.
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              Tumstatin, an endothelial cell-specific inhibitor of protein synthesis.

              Tumstatin is a 28-kilodalton fragment of type IV collagen that displays both anti-angiogenic and proapoptotic activity. Here we show that tumstatin functions as an endothelial cell-specific inhibitor of protein synthesis. Through a requisite interaction with alphaVbeta3 integrin, tumstatin inhibits activation of focal adhesion kinase (FAK), phosphatidylinositol 3-kinase (PI3-kinase), protein kinase B (PKB/Akt), and mammalian target of rapamycin (mTOR), and it prevents the dissociation of eukaryotic initiation factor 4E protein (eIF4E) from 4E-binding protein 1. These results establish a role for integrins in mediating cell-specific inhibition of cap-dependent protein synthesis and suggest a potential mechanism for tumstatin's selective effects on endothelial cells.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                October 2003
                17 November 2004
                : 95
                : 2
                : e79-e86
                aDepartment of Medicine and Clinical Science, Okayama University Graduate School of Medicine and Dentistry, Okayama, and bCenter for Tsukuba Advanced Research Alliance, University of Tsukuba Research Laboratory, Tsukuba, Japan
                73675 Nephron Exp Nephrol 2003;95:e79–e86
                © 2003 S. Karger AG, Basel

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                Figures: 5, References: 30, Pages: 1
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