Foundation and Scope

Tulane University Health Science Center was recently awarded a grant from the Louisiana Board of Regents Millennium Trust Health Excellence Fund in the amount of over $3.4 million to help establish its Hypertension and Renal Center of Excellence. Over the last few years, the Hypertension and Renal Research Group at Tulane has assembled talented investigators from the School of Medicine and the School of Public Health and Tropical Medicine who are trained using state-of-the-art experimental technologies. Our vision is to create and develop a center in order to reduce comorbidity associated with hypertension, and thus, bring improved health care and health awareness to the citizens of Louisiana.

The Center utilizes a multi-disciplinary approach to study the renal, vascular, and transport derangements and environmental factors leading to impairments in sodium excretion, enhanced vascular contractility, and hypertension. The overall rationale for the creation of the Hypertension and Renal Center of Excellence is to establish a vertically integrated research, clinical, and educational program that will lead to new research initiatives and the development of new strategies for the prevention and treatment of hypertension and its associated sequelae. To achieve these goals, emerging technology will be utilized including gene targeted mouse models and DNA gene array technology. The coordination of effort among investigators that have similar interests will allow rapid translation of developments in basic science into clinically useful diagnostic and treatment approaches so that we can reduce the burden of hypertension on the citizens of Louisiana.

Projects

The investigators of the HRCE have proposed studies that will address the broad spectrum of major current issues related to the mechanisms responsible for the development and maintenance of hypertension. The two components of this project are focused on alterations in renal vascular and transport function because of the central role exerted by the kidneys in the pathophysiology of hypertension.

It is now widely accepted that alterations in kidney function, due either to primary renal disease or to inappropriate hormonal influences on the kidney, underlie all forms of hypertension. Strong support for the role of the kidney in the development of hypertension comes from renal transplantation studies in humans and experimental animal models of hypertension. It has been shown that when hypertensive subjects are transplanted with a well functioning kidney from a normotensive donor, their hypertension is resolved. Additionally, all experimental animal models of hypertension exhibit a reduced ability of the normal blood pressure to excrete sufficient salt and water and maintain normal extracellular fluid volume.

In many situations, inappropriate activation of the renin-angiotensin system (RAS) is a major factor leading to hypertension. However, the impact of an inappropriately elevated renin-angiotensin system may be variable because of the modulating influence of several very important systems including natriuretic peptides, bradykinin, and nitric oxide that interact with or provide a counteracting balance to the actions of the RAS. From a physiological perspective, various humoral, neural, and environmental influences can shift the balance in favor of sodium retention and vasoconstriction. Some of these influences can directly affect the sodium transport proteins along the nephron. While there are important protective mechanisms that can be activated, if they are inadequate, the final outcome is still hypertension. Thus, it is equally essential to appreciate and understand the impact of these counteracting protective mechanisms.

Component A: Hypertensinogenic Mechanisms related to the RAS and counteracting mechanisms

The RAS is a critical endocrine/paracrine system that plays a major role in pathophysiology of hypertension and in the progressive renal and vascular injury that results from untreated, uncontrolled hypertension. The overall objective of this component is to characterize and establish the interactions among the multiple renal/hormonal mechanisms responsible for the development and maintenance of hypertension and those involved in providing counteractive protective influences. The underlying premise is that when the capacity of the kidneys to properly regulate sodium excretion is diminished by inappropriately elevated ANG II levels, there is an impaired regulation of blood volume which, in the face of the vasoconstrictor influences caused by elevated ANG II activity, leads to hypertension. An excessive influence of ANG II dependent mechanisms can also occur when there is an inadequate response of powerful counteracting vasodepressor mechanisms such as bradykinin, atrial natriuretic peptide, endothelial derived, or other vasodilator factors.

Component B: Mechanisms of "Volume-Dependent" Hypertension

Hypertension can be conceptualized to derive from either vasoconstrictor or volume-dependent mechanisms. Other investigators label these "low renin" and "high renin" hypertension. "Low renin" hypertension would represent an expanded intravascular volume state, in which renin secretion is suppressed. Both mechanisms can also co-exist in some patients with essential hypertension in which there is not a clearly identifiable single cause. Up to 30-40% of persons with hypertension probably have the volume-dependent mechanism of elevated blood pressure. Volume expansion results from increased sodium reabsorption, and accordingly, this component will focus on the major sodium transport proteins along the nephron.

Goals

• Aside from the obvious scientific benefits of the HEF, we also anticipate that the implementation of the HRCE with a specific administrative infrastructure will yield the following tangible accomplishments:·
• Coordinate public education efforts on the dangers of hypertension and on detection and management strategies
  
• Coordinate a network of all investigators involved in hypertension and renal research in our region
  
• Coordinate city and statewide series of conferences
  
• Develop a transgenic animal facility dedicated to specific models that are useful in hypertension research.
  
• Create an analytical and immunocytochemistry facility with services utilizing High Performance Liquid Chromatography (HPLC), radioimmunoassay, immunocytochemistry, and other associated analytical needs.
  
• Improve infrastructure of the gene array core facility by providing personnel dedicated to the application of gene array technology to hypertension related research projects.
  
• Enhancement of industrial ties with pharmaceutical companies to permit dissemination of transitional discoveries.
  Increased recruitment of highly qualified quality faculty and attract increased extramural support and federal funds.