Rajesh Kumar, Ph.D.

Associate Professor
Phone: 254-743-1203
Fax: 254-743-0165
Email: kumar@medicine.tamhsc.edu
Office#: 1R25
The Texas A&M Health Science Center College Of Medicine
Division Of Molecular Cardiology
1901 S. 1st Street, Bldg. 205
Temple, Texas 76504

Download  Curriculum Vitae (PDF) 

Education

Ph.D. Degree-Panjab University, Chandigarh, India, 1994

Post Doc Training: Institute of Microbial Technology, Chandigarh, India, 1994-1996.
Post Doc Training:  University of Virginia, Charlottesville, VA 1996-2000.

Research Interests

Intracellular Angiotensin II in Cardiac Pathophysiology

Angiotensin II (Ang II) is a pluripotent peptide hormone of the renin-angiotensin system (RAS). The RAS was first identified as a circulatory system, where Ang II generated in circulation maintained the salt and fluid homeostasis. Subsequent research showed presence of a complete and independent RAS in several tissues, known as local RAS. The local RAS has tissue specific effects and play important role in tissue homeostasis. The cardiac RAS participates in heart development and in adaptive/maladaptive changes associated with various stimuli such as hypertension and myocardial infarction. In response to these stimuli, Ang II is generated locally and acts on cardiac cells through specific plasma membrane receptors, AT₁ and AT₂.

We discovered that, in addition to working like a typical hormone through membrane receptors, Ang II can act from an intracellular location. The latter study was prompted by the observations of Ang II inside the cell. Whether the intracellular Ang II had any biological role, was not known.  We demonstrated, by generating Ang II intracellularly using recombinant methods, that intracellular Ang II can cause cell growth of cardiac myocytes in culture as well as cardiac hypertrophy in mice. This study was the first evidence of intracrine effects of Ang II in cardiac tissue. In addition, we also demonstrated that AT₁ receptor is not required for intracrine effects of Ang II, suggesting the possibility of novel intracellular Ang II receptors.

For intracellular actions, Ang II needs to be present inside the cells. Recently, we demonstrated that cardiac myocytes and fibroblasts synthesize Ang II intracellularly. Of major significance is that high glucose causes dramatic increase in Ang II synthesis, which is retained intracellularly, by cardiac myocytes, both in vitro and in vivo. Intracellular Ang II generation is catalyzed by renin and chymase, not ACE, in cardiac myocytes.

Non-ACE dependent synthesis and AT₁-independent actions of intracellular Ang II suggest that ARBs and ACE inhibitors would have limited applicability in conditions such as diabetes, which significantly upregulate the intracellular RAS. Indeed, we have recently demonstrated that a renin inhibitor was more effective than an ARB and ACE inhibitor in ameliorating diabetes induced cardiac myocyte apoptosis, oxidative stress, and fibrosis.

The physiological functions of Ang II are complex. There is a wealth of information on the actions of extracellular Ang II mediated by plasma membrane receptors; however, little is known about the role and mode of intracellular Ang II actions. Ang II is capable of controlling several distinct activities via different mechanisms that likely depend, at least in part, on specific cellular localization. The potential significance of intracellular Ang II action lies in i) generation of full signaling potential, ii) fine-tuning of signal generation, and iii) the formation of feedback loop; the latter may be associated with the regulation of the local RAS.

Therapeutic benefits of RAS blockade, in several cardiovascular diseases, have been demonstrated. There is, however, a possibility that current drugs block only the extracellular effects of Ang II and, thus, are only partially effective. Our studies on intracellular Ang II would provide understanding of the complete RAS, both extracellular and intracellular; which would allow better modulation of the RAS for therapeutic intervention.  

Selected Publications

Kumar R, Singh VP, Baker KM.  The intracellular renin-angiotensin system in the heart.  Curr Hypertens Reports.  11:104-110, 2009.

• Singh VP, Le B, Khode R, Baker KM, Kumar R. Intracellular angiotensin II production in diabetic rats is correlated with cardiomyocyte apoptosis, oxidative stress, and cardiac fibrosis. Diabetes. 57: 3297-3306, 2008.
• Singh VP, Baker KM, Kumar R. Activation of the intracellular renin-angiotensin system in cardiac fibroblasts by high glucose: role in extracellular matrix production. Am J Physiol Heart Circ Physiol. 294: 1675-1684, 2008.
• Kumar R, Singh VP, Baker KM. The intracellular renin-angiotensin system: implications in cardiovascular remodeling. Curr Opin Nephrol Hypertens. 17: 168-73, 2008. 
• Kumar R, Singh VP, Baker KM. The intracellular renin-angiotensin system: a new paradigm. Trends Endocrinol Metab 18: 208-214, 2007.
• Singh VP, Le B, Bhat VB, Baker KM, Kumar R. High glucose induced regulation of intracellular angiotensin II synthesis and nuclear redistribution in cardiac myocytes. Am J Physiol Heart Circ Physiol, 293: 939-948, 2007.
• Baker KM, Kumar R. Intracellular angiotensin II induces cell proliferation independent of AT₁ receptor. Am J Physiol Cell Physiol. 291: C995-C1001, 2006.
• Baker KM, Chernin MI, Schreiber T, Sanghi S, Haiderzaidi S, Booz GW, Dostal DE, Kumar R. Evidence of a novel intracrine mechanism in angiotensin II-induced cardiac hypertrophy. Regul. Pept. 120: 5-13, 2004.
• Kumar R, Eastwood AL, Brown ML , Laurie GW. Human genome search in celiac disease: mutated gliadin T-cell like epitopes in two human proteins promote T-cell activation. J. Mol. Biol. 319: 593-602, 2002.
• Kumar R, Sanghi S, Lumsden A, Dickinson D,  Klepeis V, Trinkaus-Randall V, Frierson HF, Laurie GW. cDNA and genomic cloning of 'lacritin, a novel secretion enhancing factor from the human lacrimal gland. J. Mol. Biol. 310:127-139, 2001.
• Kumar R, Lumsden AJ, Ciclitira PJ, Ellis HJ, Laurie GW. Human genome search in Celiac disease using gliadin c-DNA as probe. J. Mol. Biol. 300(5): 1155-1167, 2000.

Additional Publications

• Kumar R, Singh VP, Baker KM. Kinase inhibitors for cardiovascular disease. J Mol Cell Cardiol. 42: 1-11, 2007.

• Kumar R, Baker KM, Pan J. Cardiac and vascular renin-angiotensin systems. In: Contemporary Endocrinilogy: Hypertension and Hormonal Mechanisms, Second Edition, R.M. Carey, Ed., Humana Press Inc., Totowa, NJ, pp 23-42, 2007.

• Sanghi S, Kumar R, Smith M, Baker KM, Dostal DE. Activation of Protein Kinase A by Atrial Natriuretic Peptide in Neonatal Rat Cardiac Fibroblasts: Role in Regulation of the Local Renin-Angiotensin System. Regul. Pept. 132: 1-8, 2005.

• Denyer R, Sanghi S, Kumar R, Dostal DE. Novel aspects of mechanical signaling in cardiac tissue, In: Signal transduction and cardiac hypertrophy (Eds: Dhalla NS, Hryshko L, Kardami E, Singal PK) Kluwer Academic Publishers (Boston) pp 181-198, 2003. 

• Kumar R, Huebner A, Laurie GW. Genetic separation of human lacritin gene and triple A (Allgrove) syndrome on 12q13. Adv. Exp. Med. Biol. 506:167-174, 2002.

• Baker KM, Kumar R. Intracellular angiotensin II induces cell proliferation independent of AT₁ receptor. Am J Physiol Cell Physiol. 291: C995-C1001, 2006. 

• Sanghi S, Kumar R, Walton S, Laurie GW. Quantitation of rat lacrimal secretion: A novel sandwich ELISA with high sensitivity. Exp. Eye Res. 70: 651-658, 2000.

• Nihalani D, Kumar R, Rajagopal K, Sahni G. Role of amino terminal region of streptokinase in the generation of a fully functional plasminogen activator complex probed with synthetic peptides. Protein Science. 7: 637-648, 1998.

• Kumar R, Bansal RC, Mahmood A. In vivo effects of isatin on certain enzymes, lipids and serotonergic system of rat brain. Indian J. Med. Res. 100: 246-250, 1994.

• Kumar R, Bansal RC, Mahmood A. Inhibition of rat brain monoamine oxidase by indole-2,3-dione (isatin) and its structural analogs. Biogenic Amines 10: 473-485, 1994. 

• Kumar R, Bansal RC, Mahmood A. Isatin, an inhibitor of acetylcholinesterase activity in rat brain. Biogenic Amines.9: 281-289, 1993.

Patents

Sahni G, Kumar R, Roy C, Rajagopal K, Nihalani D, Sundaram V and Yadav M. Novel clot-specific streptokinase proteins possessing altered plasminogen activation characteristics and a process for the preparation of said proteins. Patent in USA, Europe, India   

• Laurie GW,  Sanghi S, Kumar R, Lumsden A. Ocular tear growth factor-like protein. Patent in USA, Europe, Australia.