title: A cross talk between class A scavenger receptor and receptor for advanced glycation end-products contributes to diabetic retinopathy.
abstract: In response to hyperglycemia in patients with diabetes, many signaling pathways contribute to the pathogenesis of diabetic complications, including diabetic retinopathy (DR). Excessive production of inflammatory mediators plays an important role in this process. Amadori-glycated albumin, one of the major forms of advanced glycated end-products, has been implicated in DR by inducing inflammatory responses in microglia/macrophages. Our goal was to delineate the potential cross talk between class A scavenger receptor (SR-A) and the receptor for advanced glycated end-product (RAGE) in the context of DR. We show here that SR-A ablation caused an exacerbated form of DR in streptozotocin-injected C57BL/6J mice as evidenced by fundus imaging and electroretinography. Immunohistochemical staining and RT-PCR assay indicated that there was augmented activation of proinflammatory macrophages with upregulated synthesis of proinflammatory mediators in the retina in Sr-a(-/-) mice. Overexpression of SR-A suppressed RAGE-induced mitogen-activated protein kinase (MAPK) signaling, whereas RAGE activation in macrophages favored a proinflammatory (M1) phenotype in the absence of SR-A. Mechanistic analysis on bone marrow-derived macrophages and HEK293 cell line revealed that SR-A interacted with and inhibited the phosphorylation of mitogen-activated protein kinase kinase 7, the major kinase in the RAGE-MAPK-NF-κB signaling, thereby leading to diminished secretion of proinflammatory cytokines. Our findings suggest that the antagonism between SR-A and RAGE contributes to the pathogenesis of DR by nurturing a disease-prone macrophage phenotype. Therefore, specific agonist that boosts SR-A signaling could potentially provide benefits in the prevention and/or intervention of DR.
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Center, Nanjing Medical University, Nanjing, China; and.
authors.forename: Ke
authors.initials: K
authors.lastname: Ma
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Center, Nanjing Medical University, Nanjing, China; and.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Center, Nanjing Medical University, Nanjing, China; and.
authors.forename: Chenchen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Center, Nanjing Medical University, Nanjing, China; and.
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Center, Nanjing Medical University, Nanjing, China; and.
authors.forename: Kexue
authors.initials: K
authors.lastname: Li
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Center, Nanjing Medical University, Nanjing, China; and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Center, Nanjing Medical University, Nanjing, China; and.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Li
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Center, Nanjing Medical University, Nanjing, China; and.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Center, Nanjing Medical University, Nanjing, China; and.
authors.forename: Hanwen
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Center, Nanjing Medical University, Nanjing, China; and.
authors.forename: Xudong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Center, Nanjing Medical University, Nanjing, China; and.
authors.forename: Hui
authors.initials: H
authors.lastname: Bai
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Center, Nanjing Medical University, Nanjing, China; and.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Ben
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Center, Nanjing Medical University, Nanjing, China; and.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Ding
authors.affiliation: The Affiliated Eye Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Keran
authors.initials: K
authors.lastname: Li
authors.affiliation: The Affiliated Eye Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Center, Nanjing Medical University, Nanjing, China; and.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Center, Nanjing Medical University, Nanjing, China; and qichen@njmu.edu.cn.
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics / Q000473:pathology; D003930:Diabetic Retinopathy / Q000235:genetics* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020239:Receptor Cross-Talk / Q000502:physiology*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000502:physiology*; D051117:Scavenger Receptors, Class A / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D013311:Streptozocin
chemical_list: D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D051117:Scavenger Receptors, Class A; D013311:Streptozocin
keywords: class A scavenger receptor, diabetic retinopathy; inflammation; microglia/macrophages