As a physician, Giuseppe Bianchi at San Raffaele Hospital in Milan finds it frustrating that he can only determine which antihypertensive drug will work in a given patient with a trial-and-error approach. Most of the available drugs only work in about 30 to 40 percent of the patient population, and those that do work affect the disease physiology, not the underlying molecular mechanisms. Bianchi, however, hopes to combine an understanding of the biological basis of the disease with genetic tools to find what drug works best in a particular patient.
In humans, part of the etiology of hypertension is the narrowing of the renal artery due to atherosclerosis, which contributes to an increase in blood pressure. The effect can be modeled in animals by placing clips on their arteries. If the clip is removed before any overt damage occurs, Bianchi says that everything in the animal reverts back to normal. "Our dream was to reproduce this clip mechanism with genetics," Bianchi says. "Our reasoning was that we might have some key genes that are involved in triggering hypertension just like the clip."
Following a top-down approach over the years, Bianchi and his colleagues went from studying the kidney to kidney cells to biochemical mechanisms to home in on the protein adducin. Adducin regulates the activity of the sodium-potassium pump that is integral to the excretory system; it controls the kidneys, and sodium retention and reabsorption. As adducin alone might not be enough to cause hypertension, the researchers also focused on the steroid ouabain that acts on the pump as well. "We find a point between these two apparently different targets: adducin, this protein, and ouabain, which is a steroid," he says. "Both of them regulate the function of the sodium-potassium pump on the plasma membrane that is the driving force for total sodium reabsorption."
Bianchi and his colleagues found that the anti-hypertension drug rostafuroxin, which has been shown to inhibit adducin and ouabain pathways in rats, has similar effects in human transfected cells and cell-free systems, as they report in Science Translational Medicine.
In a second study, the team looked at how newly diagnosed hypertension patients of European descent — both with and without adducin- and ouabain-related gene variants — responded to treatment with rostafuroxin and other hypertension drugs. "We found that patients carrying these gene variants, their blood pressure [was] controlled by the drug, while the same gene variants did not affect the blood pressure response to other anti-hypertensive agents," Bianchi says.
Because the study was small, Bianchi says his team is now expanding it to include patients from different ethnic and genetic backgrounds.
The genetic complexities underlying a disease should not be ignored, Bianchi says. Different gene networks could be at play in Asians versus Caucasians, he notes — for example, different genes whose products affect ouabain at different points may all contribute to hypertension.
In addition, he and his colleagues are looking at the genetic backgrounds of patients who respond or don't respond to other therapies for hypertension. The eventual goal, Bianchi says, is to produce a chip with all these different SNPs on it that "can tell you which are the drugs to give to the patient."
He also notes that, as his work shows, knowing the underlying biology of a disease can inform genetic and clinical studies and provide an important framework on which to build. "[Researchers should] try to develop something to study the association between gene variation and phenotypes," Bianchi says. "This is a real gap that today we need to fill."