My laboratory is interested in the roles of endocrine (tissue-to-tissue), paracrine (cell-to-cell), and intracrine (cytoplasmic and nuclear) angiotensin II (ANG II) and its G protein-coupled receptor (GPCR) signal transduction mechanisms in the proximal tubule of the kidney and blood pressure control. With grant support from NIH/NIDDK and NIH/NIGMS, respectively, we are currently studying: 1) the molecular and signaling mechanisms by which extracellular (circulating and intrarenally formed) ANG II is taken up by the proximal tubule of the kidney to act as an intracellular peptide, 2) high resolution confocal and/or electron microscopic localization of the internalized ANG II and its receptors in intracellular organelles and nucleus, 3) the effects and signaling mechanisms by which intracellular ANG II induces long-term genomic effects, 4) the role of the sodium and hydrogen exchanger 3 (NHE3) selectively in the proximal tubule on pressure natriuretic and blood pressure responses to extracellular and intracellular ANG II; and 5) the role and signaling mechanisms of ANG II/AT1a receptors in the regulation of urine concentration in the renal medulla.
To test our hypotheses, we use complementary state-of-the-art approaches including: 1) live cell multicolor fluorescent imaging, 2) high resolution electron microscopic autoradiography and immunohistochemistry, 3) intravital multi-photon functional imaging, 4) proximal tubule cells derived from human kidney, wild-type, AT1a (AT1a-KO) and AT2 (AT2-KO) receptor-deficient mice, 5) proximal tubule-specific knockout of AT1a receptors (PT-AT1a-KO) or NHE3 (PT-NHE3-KO), 6) proximal tubule-specific knockin or overexpression of an intracellular cyan fluorescent fusion of ANG II protein (ECFP/ANG II) or a fusion ANG II protein (fsANG II), which is secreted upon expression, and 7) gene microarrays, phosphoproteomic and western blot analyses.
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