Specific Aims

The Tulane Hypertension and Renal Center of Excellence was in 2002 awarded a grant from the National Institutes of Health in the amount of over $10.8 million in order to establish a Center of Biomedical Research Excellence (COBRE) in Hypertension and Renal Biology. COBRE is part of the Institutional Development Award (IDeA) program and is administered by the Division of Research Infrastructure of the National Center for Research Resources. The COBRE project provide unique research opportunities for the emerging leaders in hypertension by establishing an enriched environment in which to develop junior faculty in both clinical and basic hypertension research. The Tulane COBRE in Hypertension and Renal Biology has and will continue to provide multidisciplinary research in hypertension and renal biology and mentor junior faculty who, over time, will become independent, NIH funded investigators.

Past Projects & Investigators

Angiotensin Receptors in Renal Microvascular Physiology
Junior Faculty Investigator: Lisa Harrison-Bernard, Ph.D.
Dr. Harrison-Bernard had received extensive training in microcirculation as well as molecular biology of the renal renin-angiotensin system when she began her studies. She used, in her studies, transgenic mice and had developed an independent line of investigation using mice with deletion of the genes for the angiotensin II type (AT1) receptor subtypes.

Angiotensin (Ang) II has powerful effects on the kidney, which are mediated primarily by the angiotensin type 1 (AT1) receptor. There are two unique AT1 receptor subtypes in rodents, AT1A and AT1B, which cannot be distinguished using pharmacological antagonists. The human AT1 receptor amino acid sequence more closely resembles the rat AT1A than AT1B receptor. Thus, we need to know what role, if any, the AT1B receptor contributes to the overall function of the AT1 receptor paradigm. If the effects of AngII are proportional to the number of receptor sites at the cell surface, the subtype-specific mode of regulation ensures differentiated effects in different target cells via two very similar receptor subtypes using a single ligand. Thus, there is a greater need to explore AT1A receptor function in the absence of AT1B receptors and of the AT1B receptor function in the absence of AT1A receptors particularly as related to AngII regulated microvascular function in the kidney.

Angiotensin in Distal Nephron Ontogeny
Junior Faculty Investigator: Igor Iosipiv, M.D.
Dr. Igor received research training as a postdoctoral research fellow in developmental nephrology. In order to become clinically qualified, he then completed a pediatric residency and a pediatric nephrology fellowship. While his research during his fellowship was concentrated on the role of bradykinin B2 receptor in renal development, his project represented an independent line of investigation that was focused on the role of the renin-angiotensin system in distal nephron development.

Human renal malformations are the major cause of renal failure and hypertension during early childhood, accounting for approximately 30-40% of end-stage renal disease in children under 4 years of age. Recent studies indicate that inactivation of the genes encoding components of the renin-angiotensin system (RAS) in mice cause abnormalities in the development of renal pelvis and calyces. Angiotensinogen (Ao), angiotensin-converting enzyme (ACE), and AngII AT1 receptor-deficient mice demonstrate progressive widening of the calyx and atrophy of the papilla. Collectively, multiple lines of evidence suggest that intact RAS is required for nephrogenesis and the development of renal papilla. Our preliminary results indicate that Ao, AT1 and AT2 receptor proteins and ACE activity are all present in murine uretic bud (UB) cells of fetal origin and in inner medullary collecting duct (IMCD3) cells in culture, indicating that the two cell types that are commonly utilized to examine renal epithelial morphogenesis express major components of the RAS.

Heme-Heme Oxygenase-Carbon Monoxide System in Salt-Induced Hypertension
Junior Faculty Investigator: Fruzsina Johnson, M.D.
Dr. Johnson was an outstanding junior scientist who was completing a postdoctoral fellowship when she began her studies. Dr. Johnson has been involved in research studies since 1996 having completed the equivalent of a Ph.D. with first author papers in peer reviewed journals. She has also won several prestigious awards from several societies including the Council for High Blood Pressure of the American Heart Association. She represented the emerging generation of leaders in hypertension research.

Vascular endothelial and smooth muscle cells express heme oxygenase, that catalyzes the conversion of heme to biliverdin and carbon monoxide. The two major isoforms of heme oxygenase are the inducible heme oxygenase-1 and the constitutive heme oxygenase-2. Pathological conditions, including hypertension, can increase heme oxygenase-1gene expression. While carbon monoxide relaxes vascular smooth muscle, it also inhibits nitric oxide (NO) synthase (NOS) by competing with L-arginine. In isolated skeletal muscle arterioles, heme-derived carbon monoxide causes endothelium-dependent vasoconstriction that is converted to vasodilatation in the presence of an inhibitor of NOS.

The Role of Genetic Polymorphisms in the Epoxygenase Pathway in Hypertension
Junior Faculty Investigator: Albert Dreisbach, M.D.
When Dr. Dreisbach began his studies, he was a new faculty member in the Division of Nephrology who was interested in clinical investigations relevant to hypertension and renal diseases. He had extensive training doing fellowships in both Nephrology/Hypertension and Clinical Pharmacology. He also worked in the pharmaceutical industry for a time, giving him broad experience. This combination of experiences and disciplines is virtually unique and yet extremely important. His promise as an investigator is illustrated by a recent Faculty Development Award from the Pharmacueitical Research and Manufactures of America Foundation. Thus, he represetns physician-scientists performing clinical research, a group that has been reported to be dwindling an dhas been targeted special support.

Vasoactive arachidonic acid metabolites of the epoxygenase pathway, the epoxides, have been implicated in animal and human studies as factors which contribute to hypertension. The epoxide 11-12 epieicosatrienoic acid, the putative endothelium derived hyperpolarizing factor (EDHF) is formed by cytochrome P450 CYP2C9. CYP2C isozymes and epoxide hydrolase have been shown to catalyze the formation of the arachadonic acid metabolites, the epoxyeicosatrienoic acids (EETs) which are vasodilator epoxides presumed to include the endothelim derived hyperpolarizing factor (EDHF). CYP2C9 exhibits a high prevalence of genetic polymorphisms and phenotypes (up to 20% of certain populations), which may lead to altered levels of expoxides and reduced formation of EDHF in hypertensive patients. The altered vasoactive epoxide profile produced by CYP2C9, CYP2C8, and the epoxide hydrolase genetic polymorphisms may play a mechanistic role in hypertension.

Beneficial Effects of Physical Activity on Blood Pressure among African-American Females
Junior Faculty Investigator: Paul Muntner, Ph.D.
Dr. Muntner was just appointed junior faculty member in the Department of Epidemiology when he began his studies and represented the investigators involved in population sciences and prevention research. His project represented efforts related to the investigation of various etiologic factors in the pathway leading to hypertension control but was an independent line of investigation distinct from that of his mentors.

A recent meta-analysis demonstrated that physical activity reduces blood pressure in hypertensive patients. However, there is a paucity of data regarding the beneficial effects of physical activity on lowering blood pressure in female African-American hypertensive subjects. The magnitude of blood pressure reduction attributable to aerobic exercise may differ by body mass. We propose to conduct a randomized clinical trial of a physical activity program among African-American females. The age-adjusted incidence and prevalence of hypertension is substantially higher among African-American females compared to White sub-groups. The proposed clinical trial will provide much needed evidence regarding the benefits of physical activity among African-American females. Evidence of a blood pressure (BP) lowering effect from aerobic exercise in the proposed clinical trails may assist in the promotion of physical activity among African-American females.

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