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  • Research Summary for Jian-Wei Gu, MD

    Problem 1: The relation of sodium intake to high blood pressure

    A high-salt diet is one of the major risk factors in the development and maintenance of hypertension. However, the mechanisms involved in hypertension associated with high salt intake are much more complex. We first reported that physiological relevant high sodium concentrations, in addition to effects mediated by extracellular volume, have direct hypertensive actions such as induction of cardiac myoblast and smooth muscle cell hypertrophy.

    Using Sprague-Dawley rats, we have demonstrated that hypertension can be induced by a prolonged high-salt diet and that is associated with increased renal injury and significant changes in renal cytokine gene expression profiles that are closely related to the proinflammatory response, promatrix formation, endothelial dysfunction, and attenuated cell survival and differentiation. We also found that a high-salt diet decreased renal expression of vascular endothelial growth factor, whereas a subsequent study revealed that inhibition of the vascular growth factor receptor enhanced dietary salt-induce hypertension.

     SummaryPictureIII.jpg Our recent observations include:

    • VEGF is highly expressed in the kidney than the heart.
    • VEGF receptors are also expressed in renal tubular epithelial cells.
    • VEGF significantly in-creased the proliferation of cultured human renal tubular cells (HRPTEC), in which the inhibition of VEGF receptor caused a dose-related inhibition in the proliferation of HRPTEC.
    • VEGF significantly increases eNOS expression in cultured human glomerular microvascular endothelial cells.
    • VEGF also play a role to release NO in the systemic vascular system. These findings support the hypothesis that VEGF signaling is essential and unique in the kidneys for directly regulating the function and structure of renal vasculature and tubular systems, and plays a role in the systemic vascular system for regulating blood pressure. We believe that the attenuated response to vascular endothelial growth factor in the kidneys and systemic vascular system contributes to the development of dietary salt-induced hypertension. We will further test the hypothesis as indicated in the figure.

    Problem 2: Role of VEGF in breast cancer progression

    The growth and expansion of a tumor is mainly dependent on angiogenesis, the formation of new capillaries from pre-existing blood vessels. Vascular endothelial growth factor (VEGF) is the most critical regulator in angiogenesis and is commonly over-expressed in the most of tumors, in which tumor cells are under greater oxidative stress than normal cells.

    We have recently reported that VEGF and its receptors are the important biological markers for breast cancer malignancy and progression, and demonstrated that the paracrine effects (especially angiogenesis) and the autocrine effects (proliferation and migration) of VEGF are involved in promoting breast cancer progression. We also report that alcohol intake or obesity markedly increases tumor growth rate by mechanisms that involve up-regulation of VEGF pathways. Recent insights have shed light onto the interplay between VEGF and Notch signaling in angiogenesis. Clearly, inhibiting tumor angiogenesis can play a key role in cancer prevention and treatment.

    Our current research projects include: 1) postmenopausal obesity promotes tumor angiogenesis and breast cancer progression; 2) role of exercise-induced circulating angiostatic phenotype in the adipose tissue accumulation and breast cancer progression; 3) mechanisms of alcohol intake in tumor angiogenesis and breast cancer progression; 4) combination of EGCG (a green tea antioxidant) and SU11248 (a selective VEGF receptor inhibitor) to treat cancers including breast cancer; and 5) interplay between VEGF and Notch signaling in tumor angiogenesis and breast cancer progression.