The Problem
       Men are generally at greater risk for cardiovascular and renal disease than are women, particularly with regard to enhanced progression of hypertension and loss of renal function. Recent studies, using ambulatory blood pressure monitoring techniques, have shown that men have higher blood pressures than do age-matched women. Gender differences in hypertension and renal disease are also present in hypertensive rat models, such as the spontaneously hypertensive rat (SHR). Despite these gender differences in the progression of hypertension and renal disease in man and animals, the mechanisms responsible are unknown. However, castration in male rats has been shown to slow the progression of hypertension and ameliorate the loss in renal function, suggesting a role for androgens, such as testosterone, in mediating the gender differences in cardiovascular and renal disease. Our goal is to understand the mechanisms by which androgens play a role in the control of hypertension and promote the progression of renal injury.

Questions We Are Trying to Answer
       The hypothesis we are testing is that testosterone increases arterial pressure by decreasing the pressure-natriuresis relationship via direct tubular actions via the androgen receptor in the proximal tubule and by indirect mechanisms, such as activation of the renin-angiotensin system. The specific questions we plan to address are: 1. Is the gender difference in arterial pressure regulation in hypertensive models, such as the spontaneously hypertensive rat (SHR) and Dahl salt-sensitive rat on high salt diet, due to testosterone? Is pressure-natriuresis reduced to a greater extent in male hypertensive rats than female rats? What role does testosterone play in mediating the reduction in pressure-natriuresis and by what renal mechanisms? Does testosterone play a role in enhancement of proximal sodium reabsorption? 2. What is the tubular localization of the androgen receptors in the kidneys, and what role do androgen receptors play in mediating abnormal pressure-natriuresis in male hypertensive rats? 3. What role does the renin-angiotensin system play in mediating the effect of testosterone to exacerbate hypertension, promote the decline in renal function and increase glomerular injury in male hypertensives.

Experimental Approaches
       We use an integrative approach, applying methods from whole animal to molecular techniques. We are currently using the conscious, chronically catheterized rat preparation for chronic pressure-natriuresis studies. We also utilize glomerular and tubular micropuncture techniques, acute renal function measurements, cell and tissue culture, and molecular physiology techniques including measurement of mRNA by ribonuclease protection assays, Western blot analyses for protein, and biochemical assays for enzyme activity and immunohistochemistry for localization of the androgen receptors. We plan to develop in situ hybridization for localization of the androgen receptor mRNA in the kidneys of rats.

Progress of the Work
       We have finished characterizing the spontaneously hypertensive rat model of gender differences in hypertension and renal function. We have preliminary data that the androgen receptors are located in the nuclear portion of cells in the proximal tubule. We have also found that androgens do cause a hypertensive shift in the pressure-natriuresis relationship. Finally, we have preliminary data that the androgen receptor is involved in the hypertension in the male SHR. These findings continue to support our hypothesis.

Source of Support
       National American Heart Association