Public Release: 

Mice sense oxygen through their skin

Cell Press

Mice can sense oxygen through their skin, according to new evidence reported in the April 18th issue of Cell, a Cell Press publication.

In fact, the study shows that the skin plays a major role in sensing oxygen levels in the environment and in stimulating the kidney's production of erythropoietin (EPO) when oxygen concentrations drop. EPO is a hormone that ramps up production of the red blood cells that are responsible for carrying and delivering oxygen in the body via the circulatory system.

If the findings in mice hold for humans, the discovery might lead to new methods for treating anemia and other diseases that affect red blood cell counts. It might also have implications for endurance athletes, who sometimes train at high altitude or in low-oxygen tents to increase EPO and red cells, noted Randall Johnson of the University of California, San Diego.

"The fact that the skin plays a role at all in [oxygen sensing in mammals] is surprising," Johnson said.

Of course, he added, nobody would be surprised at all if the finding were in frogs. Amphibians have long been known to breathe in part through their skin. The new results therefore suggest that such a role for the skin in oxygen sensing is ancient and has been conserved in mammals.

"As it turns out, when we looked for the ion channels involved in this process in frog skin--which are also present in mammalian lungs--we found the same channels present in the skin of a mouse," he said. "No one had ever looked."

In the new study, the researchers created mice lacking one of the hypoxia-inducible transcription factors (HIF-1a) specifically in skin. HIFs are primary actors in the body's response to oxygen deprivation (a condition known as hypoxia).

Mice with the HIF-1a-deficient skin failed to produce EPO after several hours spent in a chamber filled with 10 percent oxygen, a level approximately equivalent to that at the top of Mount Everest. (At sea level, the oxygen concentration in the air is about 21 percent.) Under those conditions, normal mice show a 30-fold increase in EPO levels. Likewise, they found, a treatment that increased the activity of HIF-1a in the mouse skin led to a dramatic increase in blood EPO concentrations.

The researchers showed that the underlying physiology of the oxygen sensing response includes an increase of blood flow to the skin. Indeed, treatments of the animals' skin with nitroglycerin, which donates the natural vasodilator nitric oxide, led to a similar increase in EPO and red blood cells.

"EPO administration is a multi-billion dollar drug market for the treatment of all sorts of diseases involving low red blood cell counts," Johnson said. "The ability to manipulate red blood cell production just by changing blood flow through certain parts of the skin could be profound. We show in this study that, by just placing a little nitroglycerin patch, we were able to trigger very big increases in EPO. Whether this will turn out to be true for humans, we don't know yet."

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Researchers include Adam T. Boutin, Molecular Biology Section, Division of Biological Sciences, UC San Diego, La Jolla, CA; Alexander Weidemann, Molecular Biology Section, Division of Biological Sciences, UC San Diego, La Jolla, CA; Zhenxing Fu, Departments of Medicine, Pediatrics, and Pathology, UC San Diego School of Medicine, La Jolla, CA; Lernik Mesropian, Molecular Biology Section, Division of Biological Sciences, UC San Diego, La Jolla, CA; Katarina Gradin, Karolinska Institute, Stockholm, Sweden; Colin Jamora, Molecular Biology Section, Division of Biological Sciences, UC San Diego, La Jolla, CA; Michael Wiesener, University of Erlangen, Erlangen, Germany; Kai-Uwe Eckardt, University of Erlangen, Erlangen, Germany; Cameron J. Koch, University of Pennsylvania Medical School, Philadelphia, PA; Lesley G. Ellies, Departments of Medicine, Pediatrics, and Pathology, UC San Diego School of Medicine, La Jolla, CA; Gabriel Haddad, Departments of Medicine, Pediatrics, and Pathology, UC San Diego School of Medicine, La Jolla, CA; Volker H. Haase, University of Pennsylvania Medical School, Philadelphia, PA; M. Celeste Simon, University of Pennsylvania Medical School, Philadelphia, PA; Lorenz Poellinger, Karolinska Institute, Stockholm, Sweden; Frank L. Powell, Departments of Medicine, Pediatrics, and Pathology, UC San Diego School of Medicine, La Jolla, CA; and Randall S. Johnson, Molecular Biology Section, Division of Biological Sciences, UC San Diego, La Jolla, CA.

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