New genetic target found for diuretic therapy

July 30, 2012

Researchers at the University of Cincinnati (UC) have identified a new genetic target for diuretic therapy in patients with fluid overload—like those with congestive heart failure, liver cirrhosis or kidney failure.

These results, being presented in the July 30 advance online edition of the journal Proceedings of the National Academy of Sciences (PNAS), may lead to the first new diuretic therapy in 25 years and could help who experience diuretic resistance.

Manoocher Soleimani, MD, professor and chief in the division of nephrology and hypertension, says the role of diuretics is to increase urine output and help patients rid themselves of excess fluid when their kidneys are unable to do so.

"For the last several decades, physicians have been using diuretics either alone or in combination to help patients experiencing water retention," he says, adding that this can occur in patients with heart failure, kidney failure or other serious illnesses. "The most common diuretic used worldwide is hydrochlorothiazide, which works by inhibiting the kidneys' ability to retain water; these drugs can also be used to lower blood pressure. The reason they are so widely used is because they are mild and don't cause severe loss of fluid.

"However, they aren't effective with every patient."

In this study, researchers examined the specific segments of the kidneys, called tubules, and the salt-absorbing genes working there.

"The NaCl, or sodium-chloride, co-transporter (NCC), is targeted by hydrochlorothiazide and drugs in that class; it is located in the close proximity of the chloride-absorbing transporter pendrin, both of which absorb salt in the kidney," Soleimani says. "When pendrin is deleted from the body, there is no effect on salt excretion. We thought that pendrin was present to help NCC function in some way, and by using knockout animal models in this study, we found that these two genes cross-compensate for one another, and if NCC is not working, pendrin kicks in to do its job."

He says genetically engineered animal models without NCC had regular urine output and salt excretion; the same results occurred in models without pendrin. However, models lacking both genes lost large amounts of salt, were 40 percent smaller in size and produced an excessive volume of urine.

"In addition to experiencing major volume depletion, mice lacking both genes developed ," Soleimani says. "We were able to show that all of these problems resulted from salt wasting; when we put these models back on high-salt diets, the problems including electrolyte abnormalities and volume depletion were all corrected after just one week."

Soleimani says these findings could lead to a targeted diuretic therapy that inhibits pendrin, further helping patients with severe fluid overload who may not respond well to hydrochlorothiazide.

"By giving a pendrin inhibitor in conjunction with thiazide, a mild diuretic, it could greatly relieve fluid retention, providing another treatment option and improving patient outcomes," he says.

Explore further: Clinical trial examines benefits of, mechanisms behind ultrafiltration for heart failure

Related Stories

Clinical trial examines benefits of, mechanisms behind ultrafiltration for heart failure

February 23, 2012
University of Cincinnati cardiologists are conducting a one-of-a-kind clinical trial to determine if a dialysis-like procedure could be deemed the new standard of care for patients suffering from extensive fluid retention ...

Study clarifies link between salt and hypertension

January 11, 2012
A review article by researchers at Boston University School of Medicine (BUSM) debunks the widely-believed concept that hypertension, or high blood pressure, is the result of excess salt causing an increased blood volume, ...

Popular diabetes drugs' cardiovascular side effects explained

May 3, 2011
Drugs known as thiazolidinediones, or TZDs for short, are widely used in diabetes treatment, but they come with a downside. The drugs have effects on the kidneys that lead to fluid retention as the volume of plasma in the ...

Kidney dopamine regulates blood pressure, life span

July 19, 2011
The neurotransmitter dopamine is best known for its roles in the brain – in signaling pathways that control movement, motivation, reward, learning and memory.

Recommended for you

Study identifies genes responsible for diversity of human skin colors

October 12, 2017
Human populations feature a broad palette of skin tones. But until now, few genes have been shown to contribute to normal variation in skin color, and these had primarily been discovered through studies of European populations.

Genes critical for hearing identified

October 12, 2017
Fifty-two previously unidentified genes that are critical for hearing have been found by testing over 3,000 mouse genes. The newly discovered genes will provide insights into the causes of hearing loss in humans, say scientists ...

Team completes atlas of human DNA differences that influence gene expression

October 11, 2017
Researchers funded by the National Institutes of Health (NIH) have completed a detailed atlas documenting the stretches of human DNA that influence gene expression - a key way in which a person's genome gives rise to an observable ...

Genetic advance for male birth control

October 10, 2017
When it comes to birth control, many males turn to two options: condoms or vasectomies. While the two choices are effective, both methods merely focus on blocking the transportation of sperm.

Researchers uncover new congenital heart disease genes

October 9, 2017
Approximately one in every 100 babies is born with congenital heart disease (CHD), and CHD remains the leading cause of mortality from birth defects. Although advancements in surgery and care have improved rates of survival ...

Seeing hope: FDA panel considers gene therapy for blindness (Update)

October 9, 2017
A girl saw her mother's face for the first time. A boy tore through the aisles of Target, marveling at toys he never knew existed. A teen walked onto a stage and watched the stunned expressions of celebrity judges as he wowed ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.