Receptor for advanced glycation end products on human synovial fibroblasts: role in the pathogenesis of dialysis-related amyloidosis.
An important component of amyloid fibrils in dialysis-related amyloidosis (DRA) is beta(2)-microglobulin (beta(2)m) modified with advanced glycation end products (AGE). The amyloid deposits are located principally in joint structures, with adjacent chronic inflammatory reaction characterized by monocyte infiltration. This study examined the interaction of AGE-beta(2)m with human synovial fibroblasts and investigated the proinflammatory effects of that interaction. It was demonstrated that human synovial fibroblasts constitutively expressed the receptor for AGE (RAGE). RAGE expression was detected mainly in synovial intima and was upregulated in DRA synovium. (125)I-AGE-beta(2)m bound to immobilized human synovial fibroblasts in a specific, dose-dependent manner (K(d) of approximately 138.0 nM), and binding was inhibited by anti-RAGE IgG. Incubation of human synovial fibroblasts with AGE-beta(2)m induced degradation of this AGE-modified protein, as well as increased monocyte chemoattractant protein-1 (MCP-1) mRNA and protein expression. The amount of MCP-1 produced by AGE-beta(2)m-stimulated human synovial fibroblasts was sufficient to induce the chemotaxis of monocytes. MCP-1 synthesis resulted from engagement of RAGE, because the increase in MCP-1 synthesis was attenuated by preincubation of human synovial fibroblasts with anti-RAGE IgG. These data provide evidence of RAGE-mediated perturbation of human synoviocytes, which may be involved in the pathogenesis of inflammatory processes associated with DRA.
Hou
Fan Fan
FF
*Division of Nephrology, Nanfang Hospital, Guangzhou, People's Republic of China; Department of Surgery, Columbia University, College of Physicians and Surgeons, New York, New York; and Institute of Renal Outcomes Research and Health Policy, Duke University Medical Center, Durham, North Carolina.
Jiang
Jian Ping
JP
*Division of Nephrology, Nanfang Hospital, Guangzhou, People's Republic of China; Department of Surgery, Columbia University, College of Physicians and Surgeons, New York, New York; and Institute of Renal Outcomes Research and Health Policy, Duke University Medical Center, Durham, North Carolina.
Guo
Jun Qi
JQ
*Division of Nephrology, Nanfang Hospital, Guangzhou, People's Republic of China; Department of Surgery, Columbia University, College of Physicians and Surgeons, New York, New York; and Institute of Renal Outcomes Research and Health Policy, Duke University Medical Center, Durham, North Carolina.
Wang
Guo Bao
GB
*Division of Nephrology, Nanfang Hospital, Guangzhou, People's Republic of China; Department of Surgery, Columbia University, College of Physicians and Surgeons, New York, New York; and Institute of Renal Outcomes Research and Health Policy, Duke University Medical Center, Durham, North Carolina.
Zhang
Xun
X
*Division of Nephrology, Nanfang Hospital, Guangzhou, People's Republic of China; Department of Surgery, Columbia University, College of Physicians and Surgeons, New York, New York; and Institute of Renal Outcomes Research and Health Policy, Duke University Medical Center, Durham, North Carolina.
Stern
David M
DM
*Division of Nephrology, Nanfang Hospital, Guangzhou, People's Republic of China; Department of Surgery, Columbia University, College of Physicians and Surgeons, New York, New York; and Institute of Renal Outcomes Research and Health Policy, Duke University Medical Center, Durham, North Carolina.
Schmidt
Ann Marie
AM
*Division of Nephrology, Nanfang Hospital, Guangzhou, People's Republic of China; Department of Surgery, Columbia University, College of Physicians and Surgeons, New York, New York; and Institute of Renal Outcomes Research and Health Policy, Duke University Medical Center, Durham, North Carolina.
Owen
William F
WF
*Division of Nephrology, Nanfang Hospital, Guangzhou, People's Republic of China; Department of Surgery, Columbia University, College of Physicians and Surgeons, New York, New York; and Institute of Renal Outcomes Research and Health Policy, Duke University Medical Center, Durham, North Carolina.
D000686:Amyloidosis / Q000209:etiology*; D000704:Analysis of Variance; D015703:Antigens, CD / Q000302:isolation & purification; D015153:Blotting, Western; D018932:Chemokine CCL2 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007592:Joint Diseases / Q000209:etiology*; D008854:Microscopy, Electron; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D006435:Renal Dialysis / Q000009:adverse effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D001613:beta 2-Microglobulin / Q000494:pharmacology
D015703:Antigens, CD; D018932:Chemokine CCL2; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D001613:beta 2-Microglobulin