Jia 'Joe' Zhuo, MD, PhD

Dr. Zhuo’s 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. Supported by several grants from the NIDDK, the laboratory currently investigates: 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 proximal tubule ANG II and AT1a receptors in the pathogenesis of renal ischemia and reperfusion injury and kidney diseases.  

To test the hypotheses, the laboratory uses complementary innovative and 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, AT_1a (AT_1a-KO) and AT₂ receptor-deficient mice (AT₂-KO); 5) novel mouse models with proximal tubule-specific knockout of angiotensinogen (PT-AGT-KO), AT_1a (PT-AT_1a-KO), AT2 (PT-AT₂-KO), NPRA receptors (PT-NPR_A-KO), NHE3 (PT-NHE3-KO), and SIRT3 (PT-SIRT3-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) or AT2 receptors (mito-AT₂R/GFP); and 7) real-time RT-PCR, gene microarrays, proteomics and Western blot analyses. The new knowledge generated from these 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 or other hypertension with target organ injury by blocking not only endocrine and paracrine, but also intracellular or nuclear actions of ANG II, or by promoting the pressure natriuresis response through the inhibition of proximal tubule NHE3 in the kidney.  

Lab Members:

• Jia Long (Joe) Zhuo, M.D., Ph.D., Professor & Director
• Xiao Chun Li, M.D., M.Sc., Associate professor
• Mohammed Haque, Ph.D., Instructor
• Ana Paula Leite, Ph.D., Postdoctoral Fellow
• Liang Zhang, M.D., Ph.D., Visiting Scholar
• Nina Majid, B.S., Senior Program Coordinator

Collaborators:

• Bruce A. Molitoris, M.D., Professor of Medicine, Indiana University School of Medicine
• Jian-Xiong Chen, M.D., Professor, The University of Mississippi Medical Center
• Xinchun Zhou, M.D., Ph.D., Associate Professor, The University of Mississippi Medical Center
• Drazen Raucher, Ph.D., Professor, The University of Mississippi Medical Center