Meenakshi S. Madhur, Ph.D., M.D.

Assistant Professor

meenakshi.s.madhur@vanderbilt.edu
Faculty Appointments
Assistant Professor of Medicine Assistant Professor of Molecular Physiology and Biophysics
Education
M.D., Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VirginiaPh.D., Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VirginiaB.S., Duke University, Durham, North Carolina
Office Address
2215 Garland Avenue
P415D Medical Research Building IV
Nashville, TN 37232
Research Description
Hypertension is a leading cause of worldwide morbidity and mortality, leading to stroke, myocardial infarction, vascular disease, and chronic kidney disease. Emerging evidence from our laboratory and others indicates that hypertension is an inflammatory process in which T cells and T cell-derived cytokines play a central role. Despite this evidence, there are currently no treatments for hypertension that target the immune system. We were the first to demonstrate a critical role for the pro-inflammatory cytokine, interleukin 17A (IL17A), in angiotensin II induced hypertension and vascular dysfunction. When given angiotensin II, mice lacking IL17A have reduced blood pressure and preserved vascular function compared to normal mice. Recent data demonstrates that salt can directly influence naive T cells to differentiate into IL17 producing cells. How T cells can sense and respond to salt is unknown. My current research focus is how T cells and T cell-derived cytokines promote hypertension and renal/vascular dysfunction. Some current projects in my laboratory include:

Role of IL17 isoforms in hypertension and renal dysfunction:
There are two closely related isoforms of IL17 designated IL17A and IL17F. We have evidence that these isoforms have differential effects on hypertension and renal function. One focus of my lab is to characterize the role of IL17F in hypertension and the mechanism by which IL17 isoforms, A and F, may differentially regulate blood pressure through effects on renal and vascular function. To accomplish this, we use a combination of genetic knockout mice and neutralizing antibodies to IL17 and related proteins.

Effect of salt on T cell function in hypertension:
We and others have shown that salt can directly influence T cell differentiation into IL17 producing cells through upregulation of the salt sensing kinase, SGK1. We have created mice with deletion of SGK1 specifically in T lymphocytes to determine the effect on blood pressure and renal/vascular inflammation. Also, we have studies ongoing to determine how T cells sense and respond to salt. Interestingly, a small subset of T lymphocytes contain voltage-gated sodium channels. We collaborate with Dr. Kathy Murray's lab to perform whole cell patch clamping of T lymphocytes to investigate changes in sodium current between hypertensive and normotensive mouse and human T cells.

Immune mechanisms of aortic dissection:
Through a collaboration with Dr. Daniel Levy (Framingham Heart Institute), we have been studying the role of LNK/SH2B3 in hypertension and renal/vascular dysfunction. LNK was identified through a complex systems biology approach to be a key driver gene for hypertension. We have found that mice deficient in LNK have profound hypertension and renal/vascular inflammation. These mice are also predisposed to aortic dissection when given a saline load followed by angiotensin II. We are interested in how, and in which cell types, loss of LNK contributes to hypertension and this profound vascular dysfunction.

Effect of Abatacept on resistant hypertension in humans:
In conjunction with Drs. David Harrison and Cheryl Laffer, and through a grant from Bristol-Myers Squibb, we are performing a small pilot study in humans to determine the effect of Abatacept (which blocks T cell co-stimulation) on resistant hypertension and inflammatory parameters in humans.
Research Keywords
To investigate the role of T cells and T cell-derived cytokines in hypertension and renal/vascular dysfunction
Clinical Research Keywords
General Cardiology, Hypertension
Publications
Itani HA, McMaster WG, Saleh MA, Nazarewicz RR, Mikolajczyk TP, Kaszuba AM, Konior A, Prejbisz A, Januszewicz A, Norlander AE, Chen W, Bonami RH, Marshall AF, Poffenberger G, Weyand CM, Madhur MS, Moore DJ, Harrison DG, Guzik TJ. Activation of Human T Cells in Hypertension: Studies of Humanized Mice and Hypertensive Humans. Hypertension [print-electronic]. 2016 Jul; 68(1): 123-32. PMID: 27217403, PMCID: PMC4900908, PII: HYPERTENSIONAHA.116.07237, DOI: 10.1161/HYPERTENSIONAHA.116.07237, ISSN: 1524-4563.

Norlander AE, Saleh MA, Kamat NV, Ko B, Gnecco J, Zhu L, Dale BL, Iwakura Y, Hoover RS, McDonough AA, Madhur MS. Interleukin-17A Regulates Renal Sodium Transporters and Renal Injury in Angiotensin II-Induced Hypertension. Hypertension [print-electronic]. 2016 Jul; 68(1): 167-74. PMID: 27141060, PMCID: PMC4900947, PII: HYPERTENSIONAHA.116.07493, DOI: 10.1161/HYPERTENSIONAHA.116.07493, ISSN: 1524-4563.

Itani HA, Xiao L, Saleh MA, Wu J, Pilkinton MA, Dale BL, Barbaro NR, Foss JD, Kirabo A, Montaniel KR, Norlander AE, Chen W, Sato R, Navar LG, Mallal SA, Madhur MS, Bernstein KE, Harrison DG. CD70 Exacerbates Blood Pressure Elevation and Renal Damage in Response to Repeated Hypertensive Stimuli. Circ. Res [print-electronic]. 2016 Apr 4/15/2016; 118(8): 1233-43. PMID: 26988069, PMCID: PMC4833561, PII: CIRCRESAHA.115.308111, DOI: 10.1161/CIRCRESAHA.115.308111, ISSN: 1524-4571.

Perrien DS, Saleh MA, Takahashi K, Madhur MS, Harrison DG, Harris RC, Takahashi T. Novel methods for microCT-based analyses of vasculature in the renal cortex reveal a loss of perfusable arterioles and glomeruli in eNOS-/- mice. BMC Nephrol. 2016 Mar 3/2/2016; 17: 24. PMID: 26936597, PMCID: PMC4776352, PII: 10.1186/s12882-016-0235-5, DOI: 10.1186/s12882-016-0235-5, ISSN: 1471-2369.

Dale BL, Madhur MS. Linking inflammation and hypertension via LNK/SH2B3. Curr. Opin. Nephrol. Hypertens. 2016 Mar; 25(2): 87-93. PMID: 26717315, PMCID: PMC4763980, DOI: 10.1097/MNH.0000000000000196, ISSN: 1473-6543.

Wu J, Montaniel KR, Saleh MA, Xiao L, Chen W, Owens GK, Humphrey JD, Majesky MW, Paik DT, Hatzopoulos AK, Madhur MS, Harrison DG. Origin of Matrix-Producing Cells That Contribute to Aortic Fibrosis in Hypertension. Hypertension [print-electronic]. 2016 Feb; 67(2): 461-8. PMID: 26693821, PMCID: PMC4713264, PII: HYPERTENSIONAHA.115.06123, DOI: 10.1161/HYPERTENSIONAHA.115.06123, ISSN: 1524-4563.

Perrien DS, Saleh MA, Takahashi K, Madhur MS, Harrison DG, Harris RC, Takahashi T. Novel methods for microCT-based analyses of vasculature in the renal cortex reveal a loss of perfusable arterioles and glomeruli in eNOS-/- mice. BMC Nephrol. 2016; 17: 24. PMID: 26936597, PMCID: PMC4776352, PII: 10.1186/s12882-016-0235-5, DOI: 10.1186/s12882-016-0235-5, ISSN: 1471-2369.

Lindman BR, Tong CW, Carlson DE, Balke CW, Jackson EA, Madhur MS, Barac A, Abdalla M, Brittain EL, Desai N, Kates AM, Freeman AM, Mann DL. National Institutes of Health Career Development Awards for Cardiovascular Physician-Scientists: Recent Trends and Strategies for Success. J. Am. Coll. Cardiol. 2015 Oct 10/20/2015; 66(16): 1816-27. PMID: 26483107, PMCID: PMC4615587, PII: S0735-1097(15)05882-9, DOI: 10.1016/j.jacc.2015.08.858, ISSN: 1558-3597.

Lindman BR, Tong CW, Carlson DE, Balke CW, Jackson EA, Madhur MS, Barac A, Abdalla M, Brittain EL, Desai N, Kates AM, Freeman AM, Mann DL. National Institutes of Health Career Development Awards for Cardiovascular Physician-Scientists: Recent Trends and Strategies for Success. J. Am. Coll. Cardiol. 2015 Oct 10/20/2015; 66(16): 1816-27. PMID: 26483107, PMCID: PMC4615587, PII: S0735-1097(15)05882-9, DOI: 10.1016/j.jacc.2015.08.858, ISSN: 0735-1097.

Huan T, Meng Q, Saleh MA, Norlander AE, Joehanes R, Zhu J, Chen BH, Zhang B, Johnson AD, Ying S, Courchesne P, Raghavachari N, Wang R, Liu P, , O'Donnell CJ, Vasan R, Munson PJ, Madhur MS, Harrison DG, Yang X, Levy D. Integrative network analysis reveals molecular mechanisms of blood pressure regulation. Mol. Syst. Biol. 2015 Apr 4/16/2015; 11(1): 799. PMID: 25882670, PMCID: PMC4422556, ISSN: 1744-4292.

McMaster WG, Kirabo A, Madhur MS, Harrison DG. Inflammation, immunity, and hypertensive end-organ damage. Circ. Res. 2015 Mar 3/13/2015; 116(6): 1022-33. PMID: 25767287, PMCID: PMC4535695, PII: CIRCRESAHA.116.303697, DOI: 10.1161/CIRCRESAHA.116.303697, ISSN: 1524-4571.

Kamat NV, Thabet SR, Xiao L, Saleh MA, Kirabo A, Madhur MS, Delpire E, Harrison DG, McDonough AA. Renal transporter activation during angiotensin-II hypertension is blunted in interferon-¿-/- and interleukin-17A-/- mice. Hypertension [print-electronic]. 2015 Mar; 65(3): 569-76. PMID: 25601932, PMCID: PMC4326622, PII: HYPERTENSIONAHA.114.04975, DOI: 10.1161/HYPERTENSIONAHA.114.04975, ISSN: 1524-4563.

Saleh Mohamed, McMaster William, Madhur Meena. Lymphocyte adaptor protein LNK deficiency exacerbates hypertension and end-organ inflammation. JCI. 2015 Mar; 125(3): 1189-202.

Kamat NV, Thabet SR, Xiao L, Saleh MA, Kirabo A, Madhur MS, Delpire E, Harrison DG, McDonough AA. Renal transporter activation during angiotensin-II hypertension is blunted in interferon-¿-/- and interleukin-17A-/- mice. Hypertension [print-electronic]. 2015 Mar; 65(3): 569-76. PMID: 25601932, PMCID: PMC4326622, PII: HYPERTENSIONAHA.114.04975, DOI: 10.1161/HYPERTENSIONAHA.114.04975, ISSN: 1524-4563.

Huan T, Meng Q, Saleh MA, Norlander AE, Joehanes R, Zhu J, Chen BH, Zhang B, Johnson AD, Ying S, Courchesne P, Raghavachari N, Wang R, Liu P, , O'Donnell CJ, Vasan R, Munson PJ, Madhur MS, Harrison DG, Yang X, Levy D. Integrative network analysis reveals molecular mechanisms of blood pressure regulation. Mol. Syst. Biol. 2015 Jan; 11(1): 799. PMID: 25882670, PMCID: PMC4422556, ISSN: 1744-4292.

Trott DW, Thabet SR, Kirabo A, Saleh MA, Itani H, Norlander AE, Wu J, Goldstein A, Arendshorst WJ, Madhur MS, Chen W, Li CI, Shyr Y, Harrison DG. Oligoclonal CD8+ T cells play a critical role in the development of hypertension. Hypertension [print-electronic]. 2014 Nov; 64(5): 1108-15. PMID: 25259750, PMCID: PMC4191997, PII: HYPERTENSIONAHA.114.04147, DOI: 10.1161/HYPERTENSIONAHA.114.04147, ISSN: 1524-4563.

Wu J, Thabet SR, Kirabo A, Trott DW, Saleh MA, Xiao L, Madhur MS, Chen W, Harrison DG. Inflammation and mechanical stretch promote aortic stiffening in hypertension through activation of p38 mitogen-activated protein kinase. Circ. Res [print-electronic]. 2014 Feb 2/14/2014; 114(4): 616-25. PMID: 24347665, PMCID: PMC4186716, PII: CIRCRESAHA.114.302157, DOI: 10.1161/CIRCRESAHA.114.302157, ISSN: 1524-4571.

Norlander AE, Saleh MA, Madhur MS. CXCL16: a chemokine-causing chronic kidney disease [editorial]. Hypertension [print-electronic]. 2013 Dec; 62(6): 1008-10. PMID: 24060889, PMCID: PMC3970762, PII: HYPERTENSIONAHA.113.01954, DOI: 10.1161/HYPERTENSIONAHA.113.01954, ISSN: 1524-4563.

Madhur MS, Harrison DG. Synapses, signals, CDs, and cytokines: interactions of the autonomic nervous system and immunity in hypertension [editorial]. Circ. Res. 2012 Oct 10/12/2012; 111(9): 1113-6. PMID: 23065340, PMCID: PMC3646634, PII: 111/9/1113, DOI: 10.1161/CIRCRESAHA.112.278408, ISSN: 1524-4571.

Madhur MS, Funt SA, Li L, Vinh A, Chen W, Lob HE, Iwakura Y, Blinder Y, Rahman A, Quyyumi AA, Harrison DG. Role of interleukin 17 in inflammation, atherosclerosis, and vascular function in apolipoprotein e-deficient mice. Arterioscler. Thromb. Vasc. Biol [print-electronic]. 2011 Jul; 31(7): 1565-72. PMID: 21474820, PMCID: PMC3117048, PII: ATVBAHA.111.227629, DOI: 10.1161/ATVBAHA.111.227629, ISSN: 1524-4636.

Harrison DG, Guzik TJ, Lob HE, Madhur MS, Marvar PJ, Thabet SR, Vinh A, Weyand CM. Inflammation, immunity, and hypertension. Hypertension [print-electronic]. 2011 Feb; 57(2): 132-40. PMID: 21149826, PMCID: PMC3028593, PII: HYPERTENSIONAHA.110.163576, DOI: 10.1161/HYPERTENSIONAHA.110.163576, ISSN: 1524-4563.

Harrison DG, Vinh A, Lob H, Madhur MS. Role of the adaptive immune system in hypertension. Curr Opin Pharmacol [print-electronic]. 2010 Apr; 10(2): 203-7. PMID: 20167535, PMCID: PMC2843787, PII: S1471-4892(10)00007-X, DOI: 10.1016/j.coph.2010.01.006, ISSN: 1471-4973.

Madhur MS, Lob HE, McCann LA, Iwakura Y, Blinder Y, Guzik TJ, Harrison DG. Interleukin 17 promotes angiotensin II-induced hypertension and vascular dysfunction. Hypertension [print-electronic]. 2010 Feb; 55(2): 500-7. PMID: 20038749, PMCID: PMC2819301, PII: HYPERTENSIONAHA.109.145094, DOI: 10.1161/HYPERTENSIONAHA.109.145094, ISSN: 1524-4563.

Kawai-Kowase K, Kumar MS, Hoofnagle MH, Yoshida T, Owens GK. PIAS1 activates the expression of smooth muscle cell differentiation marker genes by interacting with serum response factor and class I basic helix-loop-helix proteins. Mol. Cell. Biol. 2005 Sep; 25(18): 8009-23. PMID: 16135793, PMCID: PMC1234309, PII: 25/18/8009, DOI: 10.1128/MCB.25.18.8009-8023.2005, ISSN: 0270-7306.

Owens GK, Kumar MS, Wamhoff BR. Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol. Rev. 2004 Jul; 84(3): 767-801. PMID: 15269336, PII: 84/3/767, DOI: 10.1152/physrev.00041.2003, ISSN: 0031-9333.

Kumar MS, Hendrix JA, Johnson AD, Owens GK. Smooth muscle alpha-actin gene requires two E-boxes for proper expression in vivo and is a target of class I basic helix-loop-helix proteins. Circ. Res [print-electronic]. 2003 May 5/2/2003; 92(8): 840-7. PMID: 12663487, PII: 01.RES.0000069031.55281.7C, DOI: 10.1161/01.RES.0000069031.55281.7C, ISSN: 1524-4571.

Kumar MS, Owens GK. Combinatorial control of smooth muscle-specific gene expression. Arterioscler. Thromb. Vasc. Biol [print-electronic]. 2003 May 5/1/2003; 23(5): 737-47. PMID: 12740224, PII: 01.ATV.0000065197.07635.BA, DOI: 10.1161/01.ATV.0000065197.07635.BA, ISSN: 1524-4636.

Jung F, Johnson AD, Kumar MS, Wei B, Hautmann M, Owens GK, McNamara C. Characterization of an E-box-dependent cis element in the smooth muscle alpha-actin promoter. Arterioscler. Thromb. Vasc. Biol. 1999 Nov; 19(11): 2591-9. PMID: 10559000, ISSN: 1079-5642.

Krassowska W, Kumar MS. The role of spatial interactions in creating the dispersion of transmembrane potential by premature electric shocks. Ann Biomed Eng. 1997 Nov; 25(6): 949-63. PMID: 9395041, ISSN: 0090-6964.

Available Postdoctoral Position Details
Posted: 8/8/2014
Post-doctoral position available for a PhD or MD interested in immune mechanisms of hypertension, vascular disease, and renal dysfunction. Looking for someone with experience working with rodents and basic molecular biology skills (PCR, western blotting, etc). Experience with flow cytometry is helpful but not required.