SALT LAKE CITY – University of Utah genetic researchers who
pinpointed a gene involved with an inherited form of common high
blood pressure have made significant progress in understanding how
the gene works. Scientists have unraveled a system in human kidneys
that balances dietary salt and body fluid volume and regulates
blood pressure. This new finding will make it possible to design
new drugs to treat specific causes of the common disorder.
The work was led by Jean-Marc Lalouel, a Howard Hughes Medical
Institute Investigator and faculty at the University of Utah
Department of Human Genetics. The new findings are reported in the
December issue of Hypertension, the leading periodical in
hypertension research published by the American Heart
Association.
Essential hypertension, or elevated blood pressure of unknown
cause, occurs in 50% of the people of the United States over their
lifetime. It represents a significant risk for heart attack,
stroke, and kidney failure. While the condition has genetic cause,
environmental factors such as diet, stress and exercise contribute
to its development. This complex interplay of variable factors has
so far eluded most attempts at identifying the molecular basis of
essential hypertension. While various drugs are available for blood
pressure control, any one drug is effective in only 50% or less of
the patients, indicating a poor match between pharmacological
action and the underlying mechanism of disease.
In 1992, Lalouel’s lab, in collaboration with French
researchers, found that individual variation in the angiotensinogen
gene were associated with an inherited tendency to develop high
blood pressure. The gene was discovered by studying families with
the disorder, but at the time it was unclear how the genetic
variation caused the disease. Further work by Lalouel’s lab
has provided clues in molecular terms, suggesting that genetic
susceptibility may result from a relative impairment of salt
excretion under conditions of excess salt intake. Research suggests
that salt sensitivity may represent the persistence of a "thrifty"
trait that was once of adaptive value in early stages of human
evolution when salt was less readily available. The link between
sodium balance and angiotensinogen has remained obscure because
components of a renin-angiotensin system are expressed or found
both in the general circulation and in various tissues, including
brain, heart, liver and kidney.
The angiotensinogen gene makes the hormone angiotensin II that
plays a major role in the regulation of vascular tone and blood
volume, the two key determinants of blood pressure. The active
hormone is generated through two reactions involving two enzymes
(renin and angiotensin-converting enzyme). Taken together these
elements constitute the renin-angiotensin system. Drugs that
inhibit the formation or the action of angiotensin II are often
used in the treatment of essential hypertension.
In a new series of experiments presented in the December issue
of Hypertension, the Utah scientists describe a renin-angiotensin
system operating along the entire nephron, the filtering unit of
the kidney. Visualizing the nephron as a filtering membrane
followed by a long tubular organ converging toward the bladder, the
new findings show that: (1) angiotensinogen is secreted into the
tubular segment immediately following the filter and transits
through the entire nephron; (2) renin is expressed and secreted at
a specific site further downstream from the filter, where it can
act on the precursor to generate angiotensin II; (3) expression of
both hormone precursor and processing enzyme vary as a function of
dietary sodium. Through this mechanism, the renin-angiotensin
system may be directly involved in regulating how much salt will be
reabsorbed or excreted in urine, and as a result regulate body
fluid volume and its impact on blood pressure. It may be through
this mechanism that individual differences in angiotensinogen
mediate salt sensitivity and the propensity to develop high blood
pressure. Drugs designed to interfere specifically with this
hormonal control system may be more effective in treating the
condition than those currently available.
The work was led by Dr Jean-Marc Lalouel, Investigator of the
Howard Hughes Medical Institute and Professor in Human Genetics at
the University of Utah School of Medicine. Other key scientists
involved in the project are Andreas Rohrwasser, Ph.D. and Terry
Morgan, Ph.D., from the Department of Human Genetics, Daniel
Terreros, M.D., Ph. D., from the Department of Pathology and the VA
Medical Center, and Kenneth Ward, M.D., from the Department of
Obstetrics and Gynecology. Research support was provided by the
Howard Hughes Medical Institute and the National Heart Lung and
Blood Institute.
