Advanced glycation endproduct (AGE) receptor 1 is a negative regulator of the inflammatory response to AGE in mesangial cells.
Advanced glycation endproducts (AGE) contribute to kidney disease due to diabetes or aging by means of mesangial cell (MC) receptors, such as the receptor for AGE (RAGE), which promote oxidant-stress-dependent NF-kappaB activation and inflammatory gene expression. MC also express scavenger receptors SR-I and SR-II and AGE receptors 1, 2, and 3 (AGE-R1, -R2, and -R3), some of which are linked to AGE turnover. Because AGE-R1 expression is found suppressed in severe diabetic kidney disease, as other receptors increase, we investigated whether his molecule has a protective role against AGE-induced MC injury. A stable murine MC line overexpressing AGE-R1 (R1-MC) was generated, exhibiting a 1.8- to 2.7-fold increase in (125)I-AGE-specific binding, uptake, and degradation, compared with mock-MC. However, AGE-stimulated NF-kappaB activity and mitogen-activated protein kinase (MAPK) (p44/42) phosphorylation were found markedly suppressed in R1-MC. Additionally, AGE-stimulated macrophage chemotaxis protein 1 and RAGE overexpression were abolished in R1-MC. The effect of R1 on RAGE signaling was investigated after overexpressing RAGE in Chinese hamster ovary cells, which lack RAGE. AGE stimulation elicited NF-kappaB and MAPK activities in RAGE-Chinese hamster ovary cells; however, after cotransfection with R1, these responses were suppressed. Also, after silencing endogenous R1 in wild-type MC by R1 small interfering RNA, AGE-mediated MAPK/p44/42 activation exceeded by >2-fold that of mock-MC, consistent with loss of the activation-inhibitory properties of native AGE-R1. AGE-R1, although enhancing AGE removal, is also a distinct receptor in that it suppresses AGE-mediated MC inflammatory injury through negative regulation of RAGE, a previously uncharacterized pathway that may protect renal and other tissue injury due to diabetes and aging.
Lu
Changyong
C
Department of Geriatrics and Adult Development, Division of Experimental Diabetes and Aging, Mount Sinai School of Medicine, New York, NY 10029, USA.
He
John Cijiang
JC
Cai
Weijing
W
Liu
Huixian
H
Zhu
Li
L
Vlassara
Helen
H
D000818:Animals; D019556:COS Cells; D002460:Cell Line; D018932:Chemokine CCL2 / Q000096:biosynthesis; D005786:Gene Expression Regulation; D005920:Glomerular Mesangium / Q000166:cytology* / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000473:pathology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014162:Transfection
D018932:Chemokine CCL2; D017127:Glycation End Products, Advanced; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases