Sci. Aging Knowl. Environ., 4 August 2004
Vol. 2004, Issue 31, p. nf71
[DOI: 10.1126/sageke.2004.31.nf71]

NEWS FOCUS

Suppressed RAGE

Cell-surface receptor battles compounds that promote aging by thwarting its alter ego

Mitch Leslie

http://sageke.sciencemag.org/cgi/content/full/2004/31/nf71

A receptor protein that snares damaged molecules might spare cells from a sticky situation. According to a new study, the protein guards against harmful compounds that result from reactions between sugars and amino acids. This protective molecule helps cells absorb and destroy the ruinous sugar compounds and dampens inflammation.

Advanced glycation end products (AGEs) are glutinous accretions that arise when sugar molecules glom onto proteins and undergo chemical transformations (see "Wake Up and Smell the Maillard Reaction"). Proteins tagged with AGEs can amass inside or outside cells. Although cells often demolish them, the modified molecules can also latch onto a cell-surface receptor called RAGE, triggering a cycle of destruction. RAGE activates a molecular pathway that provokes inflammation and spurs the release of reactive oxygen species, nasty byproducts of metabolism; the pathway also further stimulates RAGE, amplifying the response. AGEs accrue in the elderly and in diabetics, often damaging the kidneys, which usually neutralize them. Evidence hints that another AGE-recognizing receptor, known as AGE-R1, is protective--the protein is scarce in diabetic rodents and people. Molecular biologist Helen Vlassara of Mount Sinai School of Medicine in New York City and colleagues wanted to determine whether AGE-R1 helps combat AGEs.

The researchers genetically altered mouse kidney cells to produce two to three times the normal quantity of AGE-R1. Then, they added proteins adorned with AGEs. The engineered cells soaked up and destroyed the noxious molecules much faster than did controls, which created normal amounts of the receptor. When AGEs attach to RAGE, a cell usually turns on the protein NF-{kappa}B and adds phosphate groups to another protein, p44/42, both of which help trigger inflammation. However, the engineered cells carried only about 20% as much active NF-{kappa}B as did controls, and they also contained much less phosphate-studded p44/42. The result suggests that AGE-R1 somehow short-circuits the effects of stimulating RAGE. Next, the researchers altered hamster ovary cells--which don't normally make RAGE--to manufacture copious amounts of the protein. Dousing these cells with AGE-marred proteins hiked amounts of active NF-{kappa}B and phosphorylated p44/42. However, cells modified to make excess RAGE and AGE-R1 showed almost no increase. "AGE-R1 may actually represent a unique defense system" that hinders AGE buildup and smothers inflammation and oxidation, says Vlassara.

The paper "shows for the first time that the [AGE-R1] receptor can influence RAGE," says molecular biologist Angelika Bierhaus of the University of Heidelberg in Germany. Receptors often interfere with one another by competing for the same molecule, but the solutions in the NF-{kappa}B and p44/p42-activation experiments had plenty of AGEs to go around, she says. So the results reveal the rare situation in which one receptor suppresses another, she says. The work suggests that AGE-R1 is a "safety mechanism" to protect cells against excess AGEs, says protein chemist Vincent Monnier of Case Western Reserve University in Cleveland, Ohio. A key question now, he says, is how AGE-R1 quells RAGE. Vlassara and colleagues are trying to solve that problem and to determine whether mice that make extra AGE-R1 suffer less AGE-related damage. The work might help researchers find a way to separate AGEs from aging.


August 4, 2004
  1. C. Lu et al., Advanced glycation endproduct (AGE) receptor 1 is a negative regulator of the inflammatory response to AGE in mesangial cells. Proc. Natl. Acad. Sci. U.S.A., 2 August 2004 [e-pub ahead of print]. [Abstract] [Full Text]
Citation: M. Leslie, Suppressed RAGE. Sci. Aging Knowl. Environ. 2004 (31), nf71 (2004).








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