Research | FMP | 30-01-2020

Gene mutation in the chloride channel causes high blood pressure

Excessive production of the hormone aldosterone by the adrenal glands leads to high blood pressure and may also damage the kidneys. A team of researchers has now shown that a genetic mutation in a chloride channel triggers this disease.

Calcium measurements of aldosterone-producing cells of the adrenal gland. If the cells are blue in color, this indicates low calcium concentration. Green to red cells have increased calcium concentration, which results in the production of aldosterone. | Image: Audrey H. Soria

The steroid hormone aldosterone, in concert with other mechanisms, controls our blood pressure. It is secreted by the adrenal glands and regulates the water and salt balance in the body. Adrenal glands in patients affected by hyperaldosteronism produce excessive amounts of aldosterone, which leads to excessive sodium retention which in turn increases the excretion of potassium. In the end, this leads to abnormally high blood pressure, “arterial hypertension.” The combination of high aldosterone concentration and high blood pressure often results additionally in kidney damage.

The pathological mechanisms of the disease were incompletely understood until recently. In 2018, two international teams of researchers, one around Maria Christina Zennaro (INSERM Paris) and Thomas Jentsch (FMP and MDC, Berlin) and the other around Ute Scholl (BIH Berlin) and Rick Lifton (Rockefeller, New York), found mutations in the ClC-2 chloride channel in some patients affected by this syndrome. However, the pathway leading from the mutations to aldosterone overproduction had remained unclear – until researchers from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and the Max Delbrück Center (MDC) generated and analyzed a specific mouse model.

Professor Thomas Jentsch was the pioneer who discovered the first chloride channel family, including ClC-2, almost three decades ago. His team now initially investigated all known aldosteronism-causing ClC-2 mutations in vitro. They found that all these mutations that were thought to cause hyperaldosteronism drastically increased the flow of chloride through the channel.

To examine the hypothesis that increased chloride flow through ClC-2 causes hyperaldosteronism, the researchers then developed a mouse model in which ClC-2 was activated by an “artificial” mutation that had not been reported for patients. The genetically modified mice exhibited enormously increased chloride currents in aldosterone-secreting cells, which indirectly led to a large increase in aldosterone concentration in the blood of those rodents. Just as in patients, this resulted in abnormally elevated blood pressure and secondarily reduced activity of renin, a hormone that normally boosts aldosterone production. In addition to proving that an increase in chloride currents in adrenal gland cells leads to hyperaldosteronism, the researchers investigated the pathological pathway in great detail.

“We have seen how the channel is constantly open due to these mutations, which greatly changes the electrical voltage across the membrane of the hormone-producing cell. This leads to an influx of calcium, which, in turn, causes overproduction of aldosterone,” explains FMP researcher Dr. Corinna Göppner. “With our model, we have shown for the first time in detail, step by step, what exactly happens in the organism due to the mutated chloride channel,” the biologist continues. “As such, our findings complement and extend the human genetic findings excellently.”

Text: Beatrice Hamberger


Pathogenesis of hypertension in a mouse model for human CLCN2 related hyperaldosteronism
Corinna Göppner, Ian J. Orozco, Maja B. Hoegg-Beiler, Audrey H. Soria, Christian A. Hübner, Fabio L. Fernandes-Rosa, Sheerazed Boulkroun, Maria-Christina Zennaro, Thomas J. Jentsch.
Nature Communications 2019, 15 Oct.
doi: 10.1038/s41467-019-12113-9


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