News Release

Ten new candidate genes associated with salt sensitivity and hypertension are identified in rats

Peer-Reviewed Publication

American Physiological Society

New Orleans, LA -- The cause of most hypertension is unknown, thus, there is no cure. Worldwide control rates are poor, and less than one-fifth of the 500 million affected people have their pressures adequately controlled through treatment.

Background
Dietary salt intake is one of the most important environmental determinants of human hypertension. In as many as one third of hypertensive patients, known as “salt-sensitive hypertensives,” blood pressure is associated with dietary salt content. This is because when salt and water levels increase around cells, the excess is drawn into the blood, which is filtered by the kidneys. The kidneys remove excess salt and water from the blood, both of which are excreted as urine. When the kidneys don't work well, fluid builds up around cells and in the blood. When there is excess fluid in the blood, the heart works harder and blood pressure increases because there is more pressure on the walls of the blood vessels. This extra work weakens and wears out the heart.

Studies over the years have shown that people have adapted and can remain healthy on sodium intakes of 200 mg or even less. But with the advent of fast foods, convenience foods and processed foods, there has been an increasing trend in the amount of salt consumed in a person’s daily diet. The average consumption of sodium today amounts to about 8-15 g of salt (sodium chloride). The consequence of this trend is that more of the public is resorting to low-salt diets, assuming that such a course of action will result in lower blood pressure. This may not bring about expected results.

Great Inter-Individual Variability to Salt There is great inter-individual variability of blood pressure in the response to salt with some individuals experiencing no increase on a high salt diet while others have a significant increase on a moderate salt diet. Determining which patients will benefit from a low salt diet is a primary goal that will assist in identifying an optimum treatment regimen for those suffering from hypertension.

Scientists have determined that the body’s overall response to salt is genetically determined, and there is overwhelming evidence multiple genes are involved. To date, only genes causing rare forms of salt-sensitive hypertension have been detected and do not account for the vast majority of cases of salt-sensitive hypertension. The identification of the genetics of salt-sensitive hypertension has become a major goal.

A new research effort has used a global gene screening tool, DNA microarrays, and salt-sensitive and salt-resistant rat strains to identify genes associated with salt-sensitivity. The results of this effort will be discussed in detail during the presentation of “Effects of Dietary Salt on Gene Expression in the Rat Kidney.”

The principal investigator of the study was Dr. Robert S. Danziger, University of Illinois, Department of Medicine, Division of Cardiology, West Side VA. Co-investigators were Mariam Farjah and David Geenen at the University of Illinois; Jennifer A. Couget in Bauer Center for Genomics Research, Harvard University; Cheng Li and Wing Wong in the Biostatistics Department at Harvard. They will present their findings in detail during the American Physiological Society (APS) annual meeting, which is being held as part of the Experimental Biology (EB ’02) meeting. More than 12,000 scientific investigators are attending the conference, which begins April 20-24, 2002 at the Ernest N. Morial Convention Center, New Orleans, LA.

Methodology
A powerful new approach, transcriptional profiling using DNA microarrays, was used to probe the genetics of hypertension in general and salt-sensitivity in particular. This is the same methodology that is being used to study other complex diseases such as cancer and schizophrenia. This approach permits the expression of thousands of genes in a tissue or cell to be simultaneously analyzed. It is based upon Southern blot technology in which DNA, separated on the basis of size and charge, is transferred to a nylon membrane and hybridized to a gene-specific radiolabeled probe.

The study methods utilized an oligo-based microarray of the rat genome, on which DNA is directly synthesized on a glass substrate using photolithography and to which labeled complementary RNA (cRNA) is hybridized and then detected. Tens of thousands of sequences can be placed on a glass slide a few square inches in size.

Computational analysis has been developed to seek structure, in the form of clusters of like gene expression patterns, among different transcriptional profiles. The most prominent developing approach has been to detect similarities and dissimilarities between transcriptional profiles using repetitive hierarchical and non-hierarchical approaches to assign gene expression patterns to “clusters.” Clusters may then be compared by transcriptional profiles from different tissues, diseases or disease states, to identify common and distinguishing gene expression patterns allowing us to further understand the functional significance of these genes and the proteins they encode.

Therefore, this research study required the comparison of transcriptional profiles of kidney from two strains of rat, salt-resistant normotensive and salt-sensitive hypertensive, on high and low salt diets. To discover genes that cause salt-sensitive hypertension, identification of gene clusters unique to salt-sensitive rat strains was performed.

Results
A total of 32 genes were identified that are regulated by dietary salt through the transfer of genetic code information. Of these, 10 novel genes were determined to be particularly good new candidates for salt-sensitive hypertension since they had differential transcriptional regulation in salt-resistant normotensive versus salt-sensitive hypertensive rats strains.

Conclusions
The research used DNA microarrays to identify novel genes involved in the physiological adaptation to dietary salt, a known factor in human hypertension.

· By comparing transcriptional profiles of kidneys from salt-sensitive and salt-resistant strains of rat, at least 10 new candidates for salt-sensitive hypertension have been identified.

· These include a number of genes previously not known to be involved in salt handling or blood pressure.

· These findings do not suggest that patients with hypertension should assume that their genetic composition would allow increased sodium intake. However, the results may lead to the identification of the major genes associated with salt-resistance and salt-sensitive hypertension.

Therefore, this work may determine new therapeutic approaches to based on genetics and new targets for common forms of hypertension in humans.

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The American Physiological Society (APS) is one of the world’s most prestigious organizations for physiological scientists. These researchers specialize in understanding the processes and functions underlying human health and disease. Founded in 1887 the Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals each year.

Contact: Donna Krupa
Or 703.967.2751 (cell) or djkrupa1@aol.com Through April 19th, 2002

APS Newsroom: April 20-24, 2002
Morial Convention Center, New Orleans
Room: Level 2, Room B211
Telephone: 504.670.6534


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