My laboratory is interested in studying the roles of endocrine (tissue-to-tissue), paracrine (cell-to-cell), and intracrine (endosomal, mitochondrial and nuclear) angiotensin II (ANG II) and its G protein-coupled receptor (GPCR) signal mechanisms in the proximal tubules of the kidney and blood pressure control. With new grant supports from NIH/NIDDK and NIH/NHLBI, we are currently investigating: 1) the molecular and signaling mechanisms by which circulating and paracrine ANG II is taken up by the proximal tubule of the kidney to act as an intracellular peptide; 2) high resolution confocal and electron microscopic autoradiographic localization of the internalized ANG II and its receptors in intracellular organelles including endosomes, mitochondria and nucleus; 3) the effects and signaling mechanisms by which intracellular ANG II induces long-term genomic or transcriptional effects; 4) the role of the sodium and hydrogen exchanger 3 (NHE3) in the proximal tubule of the kidney on pressure natriuresis and blood pressure responses to paracrine and intracellular ANG II; and 5) the role and signaling mechanisms of ANG II and 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 confocal 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 receptor-deficient mice (AT2-KO); 5) novel mouse models with proximal tubule-specific knockout of AT1a (PT-AT1a-KO), AT2 (PT-AT2-KO), NPRA receptors (PT-NPRA-KO), or NHE3 (PT-NHE3-KO); 6) proximal tubule-specific, mitochondria- or nucleus-targeting overexpression of an intracellular cyan fluorescent fusion of ANG II protein (mito- or NLS-ECFP/ANG II); and 7) real-time RT-PCR, gene microarrays, phosphoproteomic and Western blot analyses.
The new knowledge generated from our studies may lead to the shift of current renin-angiotensin paradigms and aid the development of new classes of multifunctional drugs to treat ANG II-dependent hypertension associated with target organ damage by blocking not only endocrine and paracrine, but also intracellular or nuclear actions of ANG II.
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