Faculty

Jia L. Zhuo, MD, PhD

Professor of Pharmacology and Medicine
Office: G759
(601) 815-6765
Fax: (601) 984-1637

Research interests

  • New frontiers of endocrine, paracrine, and intracrine angiotensin II research
  • The mitochondrial and nuclear renin-angiotensin systems in the proximal tubule
  • G protein-coupled angiotensin II receptor pharmacology and signaling
  • Roles of proximal tubule NHE3 in pressure natriuresis and hypertension

Current research

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.

Selected recent publications (>110)

  • Li, X.C., Zhang, J.F., and Zhuo, J.L. The vasoprotective axes of the renin-angiotensin system: physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases. Pharmacol Res 125(Pt A):21-38, 2017
  • Li, X.C., Zhang, J.F., and Zhuo, J.L. Recent updates on the proximal tubule renin-angiotensin system in angiotensin II-dependent hypertension. Curr Hypertens Rep 18(8):63, 2016.
  • Zhuo, J.L., Kobori, H., Li, X.C., Satou, R., Katsurada, A., and Navar, L.G. Augmentation of angiotensinogen expression in the proximal tubule by intracellular angiotensin II via AT1a/MAPK/NF-B signaling pathways. Am J Physiol Renal Physiol. 310(10): F1103-12, 2016.
  • Roman, R.J., Fan, F., and Zhuo, J.L. Intrarenal renin-angiotensin system: locally synthesized or taken up via endocytosis? Hypertension 67(5):831-3, 2016.
  • Li, X.C., Shull, G.E., Miguel-Qin, E., Chen, F., and Zhuo, J.L. Role of NHE3 in angiotensin II-induced hypertension in NHE3-deficient mice with transgenic rescue of NHE3 in small intestines. Physiol Report. 3(11), 2015 pii: e12605.
  • Li, X.C., Shull, G.E., Miguel-Qin, E., and Zhuo, J.L. Role of the Na+/H+ exchanger 3 in angiotensin II-induced hypertension. Physiol Genomics 47(10):479-487,
  • Zhuo, J.L. SH2B3 (LNK) as a novel link of immune signaling, inflammation, and hypertension in Dahl salt-sensitive hypertensive rats. 65(5):989-90, 2015.
  • Li, X.C., Gu, V., Miguel-Qin, E., and Zhuo, J.L. A novel role of caveolin 1 in AT1a receptor-mediated uptake of angiotensin II by proximal tubule cells. American journal of physiology renal physiology 307(8):F949-F961, 2014.
  • Li, X.C. and Zhuo, J.L. Mechanisms of AT1a receptor-mediated uptake of angiotensin II by proximal tubule cells: a novel role of the multi-ligand endocytic receptor megalin. American journal of physiology renal physiology 307(2):F222-F233, 2014.