Does The Body’s Synthesis Of Certain Substances Affect The Relationship Between Obesity And Blood Pressure?

(Augusta, GA) – The number of overweight Americans has reached record levels, and  obesity now affects almost one in three citizens. Published findings from the 1999-2000 report of the National Health and Nutrition Examination Survey (NHANES), the definitive measure for weight matters in the United States, show that 59 million (31 percent) of adults are obese.  One third of adult women are obese (33 percent), a rate slightly above men (28 percent). While there is little difference in obesity rates among men across racial/ethic lines, obesity rates for African-American, Mexican-American and white female are 50, 40 and 30 percent, respectively.

One reason obesity is considered a serious health problem is because it is an important factor for essential hypertension (high blood pressure with no identifiable cause). The exact mechanisms for obesity to cause essential hypertension are not fully understood, but it has been linked to the kidneys. These organs play a key role in blood pressure and other substances which affect renal salt and water excretion, are important modulators of hypertension. 

A New Study

One fatty acid --  arachidonic acid – is an endogenous fatty acid containing 20 carbons and 4 double bonds. It can be metabolized by cytochrome P450 (CYP) enzymes into different metabolites (“eicosanoids") in the kidneys. These eicosanoids have been shown to cause constriction or dilation of the blood vessels and affect the ion transport in the nephron, the basic unit of the kidneys. Based on the functions of these eicosanoids, a team of researchers has hypothesized that the synthesis of these substances is affected during obesity and that the substances are involved in the regulation of renal function and blood pressure in obesity.

The researchers are Mong-Heng Wang, Anita Smith, Yiqiang Zhou, Hsin-Hsin Chang, Songbai Lin, and Anne M. Dorrance, all of the Department of Physiology, Medical College of Georgia, Augusta, GA. They will report on the results of their study entitled “Down Regulation of Renal CYP-derived Eicosanoids Synthesis in Fat Rats” during the upcoming scientific conference, Understanding Renal and Cardiovascular Function Through Physiological Genomics, a conference of the American Physiological Society (APS) (www.the-aps.org).  The meeting is being held October 1-4, 2003 at the Radisson Riverfront Hotel and Convention Center, Augusta, GA.

Methodology

Three-week old male Sprague-Dawley rats were split into two groups: high fat (HR) rats, fed a modified chow containing 36% fat and control rats, which were fed normal chow.

The studies were carried out on 13-week old rats, and animals were fasted overnight prior to use. Blood pressure was measured after ten weeks of treatment, and only HF rats confirmed to be hypertensive were used in the study. The blood pressure was determined by tail-cuff method and all animals were maintained on a 12-hour light dark cycle and housed two to a cage.

After 10 weeks of treatment, the animals were sacrificed, and renal tissues (cortex, medulla, and papilla) and blood vessels were isolated for the measurements of the synthesis of eicosanoids and expression of CYP enzymes.  The measurement of the synthesis of eicosanoids was conducted by HPLC method, and the expression of CYP enzymes was conducted by Western blot analysis. Data are expressed as mean ± SE.  All data were analyzed by a one-way analysis of variance or the Student’s t-test for unpaired samples.  Statistical significance was set at p<0.05.

Results

After  ten weeks of treatment, the researchers found that:

• HF rats showed significantly higher systolic blood pressure, body weight, and fat:body weight ratio;  

• the activity for 20-hydroxyeicosatetraenoic acid (20-HETE, the major eicosanoid) synthesis was decreased by 46% in cortex, 43% in medulla, and 46% in papilla of HF rats;

• activity for epoxyeicasatrienoic acids (EETs, the minor eicosanoids) was decreased by 46% in cortex, 31% in medulla, and 56% in papilla of HF rats. Interestingly, the changes in the rate of 20-HETE and EETs formation in different renal zones were consistent with the levels of expression of CYP4A and CYP2C23 proteins, respectively.  Furthermore, there were no significant changes in the synthesis of these metabolites in the renal microvessels.

Conclusions

These results demonstrate that high fat diet causes the down regulation of CYP4A and CYP2C23 in renal tubules, and these proteins are responsible for renal 20-HETE and EETs formation. Since 20-HETE and EETs are known to inhibit sodium transport in the nephron, the downregulation of the synthesis of these eicosanoids can result in an increase of sodium reabsorption and sodium retention, which is responsible for the elevation of blood pressure.

Significance of the Findings

This study is the first to demonstrate that the synthesis of these eicosanoids and the expression of enzymes that catalyze their formation are altered in the renal tubular sites after the treatment of high fat diet.  The change of the synthesis of these eicosanoids is associated with the elevation of blood pressure in HF rats.  The study calls attention to the possibility that decreased synthesis of these eicosanoids at tubular sites during the treatment of HF diet impacts on the regulation of renal function and blood pressure. 

The study also sets the basis for understanding the change of the synthesis of these eicosanoids in the renal tubular sites of fat rats, and the researchers will continue to pursue the regulatory mechanisms of this change in this animal model.  Ultimately, additional knowledge can uncover new therapeutic targets and provide new information for the control and treatment of obesity-induced hypertension.

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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 by which animals live, and thus ultimately underlie human health and disease.  Founded in 1887 the Bethesda, MD-based Society has more than 11,000 members and publishes 3,800 articles in its 14 peer-reviewed journals each year.

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EDITOR’S NOTE: Members of the press are invited to attend the conference and interview the researchers in person or by phone. Please contact Donna Krupa at (703) 527-7357 (office); (703) 967-2751 (cell) or djkrupa1@aol.com (email) for more information.