Helping Knock Out Diabetes Insipidus

By Amy Iadarola

Something fantastic happened in 1961, in a wet rat cage in Vermont.

A laboratory rat had just given birth to a litter of 17 pups. The shavings in that cage, researchers noted, were always wet and the water bottles needed constant refilling. The researchers suspected that the pups were leaning against the bottles, causing them to leak. But in reality the pups were drinking and urinating excessively — untreated, these rats must drink the equivalent of about 70 percent of their body weight every day. The pups, the researchers would soon learn, had diabetes insipidus (DI).

The Brattleboro rat was one of the first experimental animal models of DI. Although its mutation occurred spontaneously, it was the forerunner of today's “knockout” animals, in which a key gene has been deleted by modern molecular techniques. Brattleboro rats lack the hormone vasopressin and therefore, they drink and urinate constantly. Study of these unique animals has important implications for people with DI; these rats have been used, for example, to test the action of DDAVP, and more recently, as a test of gene therapy for central DI (CDI, or neurogenic DI).

HISTORY OF THE BRATTLEBORO RAT

Dr. Henry Schroeder was raising a colony of rats in West Brattleboro, VT, to study cardiovascular disease. Tim Vinton, an animal technician who helped Schroeder in his research, noticed that one cage always seemed to be wet. Schroeder and Vinton determined that six of the pups were drinking and urinating excessively. They treated the rats with vasopressin, the antidiuretic hormone that is used to treat CDI today, and the rats’ condition cleared.

Having no need for a rat that did not produce vasopressin, Schroeder passed the affected animals to colleagues at Dartmouth Medical School who were studying vasopressin, Drs. Heinz Valtin and Kurt Benirschke. With the help of another colleague, Dr. Hilda Sokol, Valtin bred the defective rats and, in addition to using the animals in their own work, Valtin and Sokol made them available to other researchers around the world.

Named after the town in Vermont in which it was discovered, the Brattleboro rat is smaller than most others. The rat’s defect was the result of a mutation in the gene that governs the production of vasopressin. Since its discovery, hundreds, or even thousands, of scientific articles on work with this genetic model have been published, and it continues to be used in numerous biomedical research laboratories around the world – even in Siberia.

VASOPRESSIN

Synthesized and stored at the base of the brain, vasopressin helps regulate kidney function. Rats and people get thirsty when the brain receives signals that the amount of water in the body is too low or that some elements in the blood, such as sodium, are too concentrated. The pituitary gland then secretes vasopressin, which travels through the blood to the kidneys, where it attaches to receptors that permit the kidneys to reabsorb water, return it to the blood, and in the process, concentrate the urine.

Because the Brattleboro rat cannot produce vasopressin, its kidneys don't return water to the blood, but instead excrete it. As a result, the rat is always drinking, in an attempt to replenish the water that was lost in the urine.

Derived from an ancient molecule, vasotocin, vasopressin was passed on to vertebrates from lower animals and even plants, for whom water balance was especially important. It is because of its antiquity, Valtin believes, that vasopressin has become so important to so many body processes. Vasopressin has acquired numerous functions during evolution, which gives it implications in the treatment of diseases and disorders other than those of the kidneys. For instance, vasopressin constricts blood vessels and therefore may play a role in regulating blood pressure. Researchers have also been investigating the role that vasopressin plays in functions of the brain, such as memory.

Says Valtin, “Whenever an investigator wants to test the possible role of vasopressin in a given function—say, of the liver, the gastrointestinal tract, or the brain—that function can be tested first in the absence of vasopressin (i.e., in an untreated Brattleboro rat) and then in the presence of vasopressin (i.e., in a Brattleboro rat after it has been given vasopressin).” It is in this way that researchers investigate the role that vasopressin plays in kidney and other functions, specifically in DI.

THE VALUE OF BASIC RESEARCH

According to Valtin, the knowledge gained from research on the Brattleboro rat and other animal models is ultimately very important toward better treatment of disease. While there are some specific medical advances that have sprung from study of the Brattleboro rat, perhaps the most valuable is simply to gain better understanding of DI. “The more we know about a system -- any system, not just the one controlling water balance -- the more likely we are to pinpoint the exact step in that system where a given disease interferes with normal function,” says Valtin, “and therefore, the more likely we are to come up with ever more specific therapy.”

APPLICATIONS

As a result of studies on the Brattleboro rat, we know why chlorpropamide is effective in the treatment of incomplete CDI. Valtin and Dr. Arnold Moses, a researcher at the University of Syracuse, showed independently that in Brattleboro rats, chlorpropamide increases the sensitivity of the kidneys to subliminal doses of vasopressin. And largely because of experiments with Brattleboro rats, researchers now know many details about the biosynthesis of vasopressin. Perhaps most directly relevant to CDI, researchers were able to identify the exact molecular defect in the so-called Brattleboro gene, which then helped in the identification of exact gene defects in human patients with CDI.

Additionally, Dr. Brad Geddes and his colleagues in England have successfully treated CDI in Brattleboro rats using gene therapy. “Their work," says Valtin, "is a good example of how experiments in the Brattleboro rat often elucidate aspects not only of CDI, but also of a much broader field—in this case, gene therapy for disorders of the central nervous system.”

Valtin encourages people with DI to remain hopeful: "Within their lifetimes we may find new, more specific and more satisfactory treatment not only for CDI but for all forms of DI," he says. "And for those forms where gene therapy becomes a reality, we might even approach cures.”

As Valtin and others continue their research on this animal model, people with DI and their loved ones watch and wait and hope that, before long, the Brattleboro rat throws a winning punch and takes DI down for the count.