AGE/RAGE Signaling in Diabetes‐Mediated Vascular Calcification in Vascular Smooth Muscle Cells

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Advanced Glycation End‐Products (AGEs)/Receptor for AGEs (RAGE) signaling cascade comprises many parts such as the complex nature of the receptor and ligand specificity. The intersecting pathways of AGE/RAGE signaling is still not well understood. AGE/RAGE signaling influences both cellular and systemic responses to increase bone matrix proteins through p38 MAPK and ERK1/2 signaling pathways in hyperglycemic and calcification conditions. AGE/RAGE signaling has also been shown to increase oxidative stress by promoting diabetes‐mediated vascular calcification through NOX‐1 activation and decreased SOD‐2 expression to promote a phenotypic switch of vascular smooth muscle cells (VSMCs) to osteoblast‐like cells. The purpose of this research is to understand AGE/RAGE mediated vascular calcification as a complication of diabetes. Calcification was induced in primary mouse VSMCs of non‐diabetic (db/wt), diabetic (db/db), non‐diabetic RAGE knockout (db/wtRKO), and diabetic RAGE knockout (db/dbRKO), and then subsequently treated with AGEs to activate RAGE. Intracellular calcium levels were quantified and showed a pronounced calcification in db/wt VSMCs and loss of RAGE resulted in a decrease in calcification in db/wtRKOVSMCs. Western blotting analysis revealed VSMC marker protein (a‐smooth muscle actin) was decreased in db/wt calcified cells. In addition, the presence of the bone marker, osteopontin (OPN), was found in both db/wt and db/wtRKO, but OPN expression was decreased with the loss of RAGE. This result indicates an osteoblast‐like phenotypic switch and this switch was negated in db/wtRKOVSMCs. These data demonstrated that RAGE has a role in diabetes‐mediated vascular calcification. By understanding the role, the AGE/RAGE signaling cascade plays diabetes‐mediated vascular calcification will allow for possible targets for pharmacological intervention to be identified that may decrease the severity of this diabetic complication.Support or Funding InformationThis research was supported by the National Science Foundation Graduate Research Fellowship Program under Grant No. 2015202674. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.