Getting inside the RAGE

All the RAGE: L-R Ms Alex Dimiropoulos, Dr Raelene Pickering,
Dr Chris Tikellis, Dr Carlos Rosado, Professor Merlin Thomas, 
Ms Maria Alejandra Zuniga-Gutierrez

Monash researchers have discovered a new way to block the effects of RAGE. No, not the angry (incredible hulk) kind of rage. But it may be just as important.

The Receptor for Advanced Glycation End-products (known as RAGE) is an important player in many diseases, from atherosclerosis and diabetes to cancer and neurodegenerative disease.
In each of these conditions RAGE kindles inflammation, cell proliferation and death. But there has been no way to block its effects.

"This is probably because all the focus on RAGE was on signalling from the outside", says Professor Merlin Thomas for the Department of Diabetes at Monash University, "but it turns out all the action is on the inside."

In an article published this week in Journal of Clinical Investigation (JCI), Monash researchers describe a new pathway by which RAGE can be transactivated by the angiotensin receptor with which it forms a complex. This pathway does not rely on extracellular signalling and likely represents the major way that RAGE is activated.

"Mice lacking RAGE are protected against atherosclerosis associated with diabetes. So we gave them back just the inside part of RAGE and this was enough to restore their sensitivity to diabetic complications," said Dr Thomas.

Using this knowledge, the researchers then developed a selective inhibitor of the inner tail of RAGE, which was able to block inflammation just as well as RAGE deletion.

With the generous support of JDRF, Diabetes Australia, the Jreissati and Meydan families, new therapeutics are currently being developed based on these discoveries that may be applicable across a broad range of conditions in which RAGE has been implicated, including diabetes, atherosclerosis, neurodegenerative diseases, malignancy, and other important conditions.

Reference:
Raelene J. Pickering, Christos Tikellis, Carlos J. Rosado, Despina Tsorotes,Alexandra Dimitropoulos, Monique Smith, Olivier Huet, Ruth M. Seeber, Rekhati Abhayawardana, Elizabeth K.M. Johnstone, Jonathan Golledge, Yutang Wang, Karin A. Jandeleit-Dahm, Mark E. Cooper, Kevin D.G. Pfleger, Merlin C. Thomas. Transactivation of RAGE mediates angiotensin-induced inflammation and atherogenesis. Journal of Clinical Investigation.

See more about Professor Thomas's research: www.monash.edu/medicine/ccs/diabetes/research/thomas-group