Advanced glycation end product (AGE) receptor 1 suppresses cell oxidant stress and activation signaling via EGF receptor

Abstract

Advanced glycation end product receptors (AGERs) play distinct functional roles in both the toxicity and disposal of advanced glycation end products (AGEs), substances that are linked to diabetes and aging. Overexpression of AGER1 in murine mesangial cells (MCs) (MC-R1) inhibited AGE-induced MAPK1,2 phosphorylation and NF-B activity and also increased AGE degradation. The mechanism of the inhibitory effects of AGER1, upstream of MAPK, was explored in MCs and HEK293 AGER1-expressing cells. AGEinduced Ras activation was found to be linked to Shc͞Grb2 complex formation and Shc phosphorylation in MCs, responses that were markedly reduced in MC-R1 cells. AGE responses also included EGF receptor (EGFR) phosphorylation in MCs or HEK293 cells, but this link was blocked in both MC-R1 and HEK293-R1 cells. Coexpression of AGER1 and EGFR in HEK293 cells decreased AGE-mediated EGFR and p44͞p42 phosphorylation but not EGF-induced p44͞p42 activation. AGE, S100͞calgranulin, or H 2O2 promoted MAPK phosphorylation in EGFR ؉ cells in a manner that was inhibitable by an EGFR inhibitor, AG1478. Also, in AGER1 cells, AGE-induced H2O2 formation and AGE-or S100-induced p44͞p42 phosphorylation were suppressed, and these effects were restored by R1 siRNA. These data confirm that R1 negatively regulates AGE-mediated oxidant stress-dependent signaling via the EGFR and Shc͞Grb2͞Ras pathway. AGER1 could serve as a model for developing therapeutic targets against vascular and kidney disorders related to diabetes and aging.phosphorylation ͉ reactive oxygen species ͉ mesangial cells ͉ MAPK ͉ diabetes

Dangers Within

“…76,112,122 In db/db mice, increased RAGE and S100 expression in podocytes associates both with renal pathology and with increased infiltration of mononuclear phagocytes to glomeruli; these effects are blocked by anti-RAGE antibody. 112 Serum RAGE levels, kidney damage, and inflammatory mediators in diabetic animals and humans are inversely related to levels of AGE receptor-1, 123,124 suggesting an anti-inflammatory protective role for AGE receptor-1 in diabetes. 123 AGE, RAGE, 97,117 and other DAMPs are also strongly implicated in the pathogenesis of nondiabetic glomerular diseases.…”

Acute Kidney Injury in Older Adults

“…116 Although data in humans are limited, levels of proinflammatory factors are higher in patients with advanced CKD 117,118 as well as mice, 119 and a cascade of chemokine production and activation of proinflammatory factors likely lead to interstitial fibrosis, CKD, and distant-organ injury. 112,113,120 Reactive oxygen species (ROS) and advanced glycation end products (AGEs) increase with age, and levels of the antiinflammatory AGE receptor AGER1, which binds and quenches excess AGEs and ROS and inactivates the proinflammatory receptor RAGE, 121,122 are reduced under chronic oxidative conditions such as aging, CKD, or type 2 diabetes. 122 In mouse studies, RAGE induces ROS and superoxide in diabetic mitochondria, 123 and the severity of AKI depends on a functioning endoplasmic reticulum stress pathway and preexisting levels of ROS.…”

Elevated Epidermal Growth Factor Receptor Phosphorylation Induces Resistance Artery Dysfunction in Diabetic db/db Mice

“…For instance, it has been shown that diabetes is associated with an increase in advanced glycation end products (AGEs) formation. It is noteworthy that AGE-induced oxidative stress increases through EGFR transactivation, which is suppressed in cells overexpressing AGEs receptor 1 (19), providing evidence for a relationship between diabetes, AGEs, EGFR, and oxidative stress.…”