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Ashok Kumar, Ph.D.

Professor of PathologyAshok Kumar

My current research interest is to understand molecular mechanisms involved in hypertension and other cardiovascular diseases with special emphasis on the role of renin-angiotensin system. Angiotensin-II is one of the most potent vaso-active substances known and is synthesized from its precursor molecule, angiotensinogen, by the combined proteolytic action of renin and angiotensin converting enzyme. Recent studies have shown that patients with essential hypertension have higher plasma angiotensinogen levels and linkage studies have suggested an association between angiotensinogen gene and essential hypertension. However, molecular mechanisms involved in increased plasma angiotensinogen level in hypertensive patients have not been clarified. The human angiotensinogen gene locus contains 25 polymorphic sites in 20 Kb region. Recent studies from our group have shown that these single nucleotide polymorphisms form distinct haplotypes that are associated with hypertension in Caucasian and African-American hypertensive subjects. Our transient transfection and gel shift analyses have identified transcription factors that bind to these polymorphic sites so as to understand their role in transcriptional regulation.

In order to understand molecular mechanisms involved in hypertension in an in vivo situation, we have generated transgenic mice that contain wild type and modified BACs containing different haplotypes of human angiotensinogen and angiotensin receptor genes. These BACs (containing 160-180 Kb of DNA) presumably contain 50-80 Kb of the promoter sequences that are required for tissue specific expression of these genes but differ only in specific single nucleotide polymorphic sites. Therefore these transgenic mice are unique to understand the role of single nucleotide polymorphisms in the promoter region of these genes on transcriptional regulation in an in vivo situation. Our studies have shown that certain haplotypes of angiotensinogen and angiotensin receptor genes increase the blood pressure in transgenic mice. Our in vivo chromatin immunoprecipitation studies have shown that increased blood pressure is correlated with increased transcription of these genes in the liver and kidney of transgenic mice. To identify the downstream effector genes that are involved in blood pressure regulation and renal and cardiac fibrosis, we have performed transcriptome analysis in the kidney and heart of transgenic mice. These studies have identified a number of genes whose expression is perturbed and are potential therapeutic targets to reduce hypertension and end organ damage.

Publications:

Sudhir Jain, Andrej Tillinger, Brahmaraju Mopidevi, Varunkumar Pandey, Steven N. Fiering, Soren Warming, and Ashok Kumar. Transgenic mice with -6A haplotype of the Human Angiotensinogen gene have increased blood pressure compared to -6G haplotype. J. Biol. Chem. 285:41172-41186 (2010). PM 20978123

Brahmaraju Mopidevi, Madhusudhan Ponnala, and Ashok Kumar: Human Angiotensinogen +11525 C/A Polymorphism Modulates Its Gene Expression Through MicroRNA Binding. Physiological Genomics 45: 901-906 (2013). PM 23943853

Varunkumar G. Pandey , Sudhir Jain, Anita Rana, Nitin Puri, Sri Krishna C. Arudra, Brahmaraju Mopidevi, Meenakshi Kaw, Alberto Nasjletti, Ashok Kumar. Dexamethasone Promotes Hypertension By Allele-Specific Regulation Of The Human Angiotensinogen Gene. J. Biol. Chem. 290:5749-5758(2015). PM 25568318

Sudhir Jain, Alicia Prater, Varunkumar Pandey, Anita Rana, Nitin Puri, Ashok Kumar. A Haplotype of Angiotensin Receptor Associated with Human Hypertension Increases Blood Pressure in Transgenic Mice. J. Biol. Chem. 288: 37048-37056 (2013). PM 24202179

Jain S, Tulsulkar J, Rana A, Kumar A, Shah ZA. Transgenic Mice Overexpressing Human Angiotensin I Receptor Gene Are Susceptible to Stroke Injury. Mol Neurobiol. 2016 Apr; 53(3):1533-1539. PM 25652270

Jain S, Puri N, Rana A, Sirianni N, Mopidevi B, Kumar A. Metabolic syndrome induces over expression of the human AT1R: a haplotype-dependent effect with implications on cardio-renal function. Am J Hypertens. 2017 Oct 5. PM 29036458

Rana A, Jain S, Puri N, Kaw M, Sirianni N, Eren D, Mopidevi BR, Kumar A. The transcriptional regulation of the human angiotensinogen gene after high-fat diet is haplotype-dependent: Novel insights into the gene-regulatory networks and implications for human hypertension. PLoS One. 2017 May 3;12(5):e0176373. PM 28467442