Mariela Mendez Ph.D.
- M.S. Biochemistry, Universidad Nacional de Córdoba, Argentina 1998
- Ph.D. Pharmacology, University of Buenos Aires School of Medicine, Argentina 2005
Summary of Research Interests
Our laboratory studies the molecular mechanisms involved in the release and exocytosis of renin-containing granules. Renin is the rate-limiting enzyme in the formation of angiotensin II, playing a dominant role in blood pressure regulation. Chronically enhanced circulating renin causes hypertension. Renin is stored in dense-core granules in juxtaglomerular (JG) cells, located at the pole of the renal afferent arteriole. Given its importance in blood pressure control, several hormonal and intrinsic mechanisms regulate renin release. These mechanisms enhance cAMP, the most potent stimuli for renin release. A very small fraction of total renin is released from JG cells even after strong stimulation. Thus the final steps in renin release are tightly controlled. We have recently shown that stimulated release of renin is mediated by members of the SNARE family of proteins, known to mediate vesicle exocytosis. Specifically we found that VAMP2 and SNAP23 are required for renin release, implicating renin-granule exocytosis as the major mechanism of release.
Our studies aim to:
- Identify the specific set of SNAREs and binding proteins that mediate cAMP-stimulated renin release.
- In addition, the mechanism by which cAMP stimulate renin involves protein kinase A (PKA). However, the molecular targets by which PKA stimulate renin release have not been elucidated. We aim to identify the molecular targets of PKA and its involvement in renin exocytosis.
- Determine the mechanisms by which oxidative stress stimulate renin release and its relationship to hypertension.
- Study the role of hyperglycemia, Type I and II diabetes in enhancing renin release, hypertension and renal cortical damage.
We use a variety of techniques to specifically study renin release and exocytosis in primary cultures of juxtaglomerular cells and isolated/perfused afferent arteriole:
- Primary cell culture of renal juxtaglomerular cells
- Molecular Biology for cloning, protein tagging and site-directed mutagenesis
- In vitro and in vivo adenovirus-mediated gene transfer to juxtaglomerular the kidney and isolated cells
- In vitro microperfusion of dissected afferent arteriole with attached glomeruli.
- Real-time (live-cell) epifluorescence, confocal and total internal reflection microscopy.
- Real time monitoring of cAMP and PKA activity using fluorescence resonance energy transference (FRET) probes.
- 2001 Fellowship Grant, American Heart Association/Michigan Affiliate.
- 2002 Fellowship Grant, American Heart Association/Michigan Affiliate.
- 2004 Winner, top award for scientific merit (cash award), Henry Ford Health System 1st Annual Research Symposium.
- 2008 Post-doctoral Fellowship, National Kidney Foundation.
- 2009-12 NIH/F32-NRSA Post-Doctoral Fellowship, National Institutes of Health.
- 2010 Finalist, APS-Renal section Excellence in Renal Research Award for post-doctoral fellows. Experimental Biology
- 2010 Travel award for Professional Development Seminar (PDS). American Society of Nephrology. Denver, CO.
- 2011 Caroline Tums Professional Opportunity Award, American Physiological Society, 2011.
- 2011 Winner, top award for scientific merit (cash award), Henry Ford Health System 8th Annual Research Symposium.
- 2011 Finalist, International Society of Hypertension-ISH New Investigators Symposium. Orlando, Florida.
- 2011 Editorial Board, American Journal of Physiology-Renal Physiology 2011-
Selected Peer Reviewed Journal Articles
- Cortes, P., Mendez, M., B.L. Riser, C.J. Guérin, A. Rodríguez-Barbero, C. Hassett, and J.F. Yee. F-actin fiber distribution in glomerular cells: structural and functional implications. Kidney Int. 58: 2452-2461, 2000.
- Mendez, M., and M.C. LaPointe. Trophic effects of the COX-2 product prostaglandin E2 in cardiac myocytes. Hypertension 39: 382-388, 2002.
- He, Q.*, Mendez, M.* and M.C. LaPointe. Regulation of the human brain natriuretic peptide gene by GATA-4. Am. J. Physiol. Endocrinol. Metab. 283: E50-E57, 2002 (* equal contribution).
- Mendez, M. and M.C. LaPointe. Inhibitory effect of PPAR? on IL-1? regulation of COX-2, PGE2 synthase and inducible nitric oxide synthase in cardiac myocytes. Hypertension 42: 844-850, 2003.
- LaPointe, M.C., Mendez, M., A. Leung, Z. Tao, and X.-P. Yang. Inhibition of COX-2 improves cardiac function and decreases collagen content in the infarcted mouse heart. Am. J. Physiol. Heart Circ. Physiol. 286: H1416-H1424, 2004.
- Giannico G, Mendez, M., LaPointe MC. Regulation of the membrane-localized prostaglandin E synthases mPGES-1 and mPGES-2 in cardiac myocytes and fibroblasts. Am J Physiol Heart Circ Physiol. 2005 Jan; 288(1):H165-74.
- Mendez, M., and M.C. LaPointe. PGE2-induced hypertrophy of cardiac myocytes involves EP4 receptor-dependent activation of p42/44 MAPK and EGFR transactivation. Am J Physiol Heart Circ Physiol. 2005 May; 288(5):H2111-7.
- Mendez, M. CBP and p300 in renin homeostasis: can they drive the fate? Am J Physiol Heart Circ Physiol. 2009 May; 296(5):H1213-4.
- Mendez, M. (corresponding author), Kenneth W. Gross, Sean T. Glenn, Jeffrey L. Garvin and Oscar A. Carretero. Expression of vesicle associated membrane proteins (VAMPs) in mouse Juxtaglomerular cells (JG): Role of VAMP 2/3 in cAMP-stimulated renin release. Journal of Biological Chemistry. 2011 Aug 12;286(32):28608-18. Epub 2011 Jun 27.
- Mendez, M., Jeffrey L. Garvin and Oscar Carretero. Role of the SNARE protein SNAP-23 on cAMP-stimulated Renin release from mouse Juxtaglomerular (JG) cells. Experimental Biology 2010. FASEB J. 2010 24:1059.24
- Paulo S. Caceres, Mendez, M. and Pablo A. Ortiz. Vesicle associated membrane protein (VAMP) 3 but not VAMP-2 is involved in apical targeting of NKCC2 and processing in rat thick ascending limbs (TAL). Experimental Biology 2010. FASEB J. 2010 24:606.32
- Mendez, M., Sean T. Glenn, Kenneth W. Gross, Jeffrey L. Garvin and Oscar A. Carretero. Expression of vesicle associated membrane proteins (VAMPs) in mouse Juxtaglomerular cells (JG): Role of VAMP 2/3 in cAMP-stimulated renin release. Council of High Blood Pressure. Washington DC, 2010. Hypertension 2010; 56; e50-e166.
- Mariela Mendez. The SNARE protein VAMP2 but not VAMP3 mediates cAMP-stimulated renin release from juxtaglomerular cells. Experimental Biology 2011. FASEB J March 17, 2011 25:665.18
- M. Cecilia Ortiz-Capisano, Mendez, M., Pablo A. Ortiz and William H. Beierwaltes. Adenosine 1 receptors are expressed by juxtaglomerular cells and interact with calcium signaling to decrease renin release. Experimental Biology 2011. FASEB J March 17, 2011 25:824.5
- Mendez, M. and Jeffrey L. Garvin. Superoxide and Hydrogen peroxide stimulate renin release from mouse Juxtaglomerular cells. Council of High Blood Pressure, September 2011. Hypertension 58(5): E98-E98.
- Mendez, M. Enhanced renin release and content in juxtaglomerular cells of VAMP8 KO mice. Experimental Biology 2012. FASEB. 2012: 26:690.20