Now, investigators from Germany at the University of Erlangen, the Max Delbr ck Center for Molecular Medicine (MDC) Berlin-Buch and Regensburg, collaborating with researchers from Finland and Austria have shed new light on the relationship between salt intake, bodily processes, and blood pressure regulation. Within the skin, they have detected a new storage area for salt in the body. They also found out that if the process behind this storage is defect, animals become hypertensive (Nature Medicine, doi 10.1038/nm.1960).

Salt (natrium chloride, NaCl) is required for life. Herbivores (plant-eating animals) risk their lives to go to "salt licks" and carnivores (meat-eating animals) go to salt licks to eat herbivores in order to obtain salt.

Salt is responsible for water regulation in the body. It is taken up by the gastro-intestinal (GI) tract and, in large part, excreted by the kidneys. However, salt is also stored in cells and in the interstitium, the area between cells in the body.

Dr. Jens Titze and colleages, among them Dominik N. M ller, Wolfgang Derer, and Friedrich C. Luft from the Experimental and Clinical Research Center at the MDC, could now show that a high-salt diet in rats leads to the accumulation of salt in the interstitium in the skin. This process is carefully regulated by special white blood cells, the macrophages.

In those macrophages, the scientists found a gene regulator (transcription factor) called TonEBP (tonicity-responsible enhancer binding protein). TonEBP is activated in these cells in response to high salt and turns on a gene (VEGF-C - vascular endothelial growth factor C) that controls the production of lymphatic blood vessels. With high-salt diet the lymphatic vessels increase.

The investigators also showed that when these macrophages are depleted or if the receptor for VEGF-C is absent, the animals are not able to "store their salt" and become hypertensive. However, this process and its relevance to human disease are not yet completely understood.

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His group studied two separate strains of mice, each carrying a specific genetic alteration that makes them especially prone to develop atherosclerosis. The mice also lacked CHOP, disabling the prodeath branch of the ER stress pathway.

When fed a diet high in fat and cholesterol for 10 weeks, one strain of those CHOP deficient mice with atherosclerosis developed smaller lesions than mice with CHOP, they report. Most importantly, cell death and plaque necrosis dropped by about 50 percent. The second strain of atherosclerotic mice showed essentially the same result.

Despite the fact that evidence had pointed to ER stress and the UPR before, Tabas said the result - and particularly the magnitude of the effect - still came as a considerable surprise.

"The fact that we were able to isolate one gene encoding one protein with such a profound effect on plaque necrosis was a big surprise," he said. That's because there could be many other processes at work, including some that might compensate for CHOP loss.

The findings in mice could have some real implications in the clinic, Tabas added.

"The results of this study, together with recent findings showing expression of CHOP in vulnerable human atherosclerotic plaques, suggest that the CHOP pathway may be a potential therapeutic target related to the formation of dangerous atheromata," the researchers concluded. "In particular, it will be interesting to determine whether so-called chemical chaperones, which have been successfully used in other animal models of UPR-associated diseases, have a beneficial effect on advanced atherosclerotic lesion progression."

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