Mechanism for Hypertension, Insulin Resistance, and Immune Suppression in Rats Revealed

Researchers have discovered a molecular mechanism in a strain of rats that explains why metabolic disorders like hypertension and diabetes often arise together in mammals. The University of California, San Diego’s Jacobs School of Engineering also showed that a common antibiotic reversed the animals’ symptoms of high blood pressure, insulin resistance, and immune suppression.

These studies indicate that hypertension and cell dysfunctions associated with metabolic syndrome may be part of an enzymatic auto-digestion process in which proteases in our body become uncontrolled and break down proteins, reports Geert Schmid-Schnbein, a professor of bioengineering.

Spontaneously hypertensive rats (SHR), a strain predisposed to develop high blood pressure, were used in the study. These rodents, like many people, develop other metabolic complications when high blood pressure arises.

The investigators found significant levels of proteases in the animals’ circulation. Natural enzyme inhibitors found in normal healthy rats did not lower the level of protease activity in the SHR strain to normal levels.

In these hypertensive rat, enzymes cleaved extracellular portions of several protein receptors such as the insulin receptor. Insulin could thus no longer bind and facilitate normal metabolism of glucose, the scientists report. The CD18 receptor, a binding receptor on the surface of infection-fighting leukocytes, was also cleaved. With the loss of CD18 receptors, leukocytes of the SHR animals were unable to bind to the wall of blood vessels, resulting in a compromised immune system, according to the researchers.

The team went on to test whether a protease-blocking drug doxycycline could reverse the multiple metabolic complications. They found that the compound halted the activity of certain proteases in the SHR rat strain.

The scientists had observed that protein receptors on the surface of SHR cells become clipped off as the animals develop hypertension. They found that after several weeks of ingesting doxycycline, however, the SHR rats developed cells that had normal CD18 and insulin receptors. The animals’ metabolic conditions simultaneously improved, blood pressure normalized, and symptoms of immune suppression disappeared, they report.

The study is published on June 30 in the online version of Hypertension.