Cause of gender differences in high blood pressure and related kidney disease

While men and women both get high blood pressure and related kidney disease, the path to get there is shorter, steeper and just different for men, researchers say.

"They may end up at the same point, but the way they got there could be very different," says Dr. Jennifer C. Sullivan, pharmacologist/physiologist at the Medical College of Georgia Vascular Biology Center.

"It's known that men tend to develop hypertension earlier than women and the increase in blood pressure occurs more rapidly than it does in women, until they hit menopause. I look at our spontaneously hypertensive rats and see the same dichotomy in blood pressure," Dr. Sullivan says of the animal model she studies. "There are also differences in development of renal injury in the human population and chronic renal disease seems to be worse in men and I see the same thing in my animal model."

She's looking at these gender differences to find what protects females, at least for much of their life, work that led to her selection for the 2007 New Investigator Award of the American Physiological Society's Water and Electrolyte Homeostasis Section. She presented her work May 1 during the Experimental Biology Meeting Annual Meeting in Washington, D.C.

Female hormones can't account for all the difference, she says. "It's not that easy. Men and women are more than just sex hormones." When she takes testicles out, for example, blood pressure and injury incidence drop some; when she takes ovaries out, blood pressure remains unchanged but kidney injury increases slightly. "There are fundamental differences, I believe, in the physiology. They are going to end up at the same point but the way there could be very different."

So she's comparing in males and females some major players in blood pressure regulation and renal injury: the potential for blood vessels to relax and constrict and the amount of damage-producing free radicals.

She's finding that nitric oxide synthase, which makes nitric oxide, a signaling molecule that tells smooth muscles cells to relax, may make more nitric oxide in females. Just how active an enzyme is depends on how it's phosphorylized, or turned on by adding phosphate groups. "Our preliminary data says that the phosphorylation status may increase nitric oxide production - and maintain kidney health - in females," Dr. Sullivan says.

In contrast is the powerful constrictor of blood vessels, angiotensin 2. In the outer most part of their kidneys, males have a lot of the AT1 receptors that enables angiotensin 2 to do harm. "It's a vasoconstrictor when it binds with AT1," she says. "It will cause proliferation, it will cause hypertrophy, it can stimulate the production of reactive oxygen species, so it does all sorts of bad things," she says.

Fortunately there are already drugs that block angiotensin 2's destructive action: angiotensin receptor blockers and ace inhibitors. Interestingly, clinical studies already have shown these drugs don't work as well in women. "A lot of women are on these drugs too and I'm not sure it's doing them a lot of good," she says. One of her goals is to find out.

When she looks in the outer most part of the kidney, called the renal cortex, she also finds males have too many highly reactive and potentially damaging free radicals. Free radicals or reactive oxygen species have important jobs in the body, like cell signaling, but as with anything, it's all about balance.

When there are too many, it creates oxidative stress, a contributor to most major diseases, such as cancer and cardiovascular disease, as well as aging in general. In high blood pressure, free radicals damage proteins critical to blood vessels and the kidneys.

The body has natural mechanisms for keeping free radicals in check, including endogenous antioxidants. "But if you get increases, it can overwhelm the natural ability of the body to take care of it," she says.

When she looks to see the toll all this takes on the kidneys, she finds about a 50 percent increase in the amount of protein excreted in the urine - a sure sign of kidney disease - in the males.

She notes that by age 70, the rates of cardiovascular disease and hypertension are similar in men and women and that older women tend to have higher blood pressures than age-matched men.