title: Pathological roles of advanced glycation end product receptors SR-A and CD36.
abstract: The pathological significance of advanced glycation end product (AGE)-modified proteins deposited in several lesions is generally accounted for by their cellular interaction via the AGE receptors and subsequent acceleration of the inflammatory process. In this study, we focused on two AGE receptors-specifically, the role of SR-A in pathogenesis of diabetic nephropathy and the role of CD36 in AGE-induced downregulation of leptin by adipocytes. In terms of SR-A, diabetic wild-type mice exhibited increased urinary albumin excretion, glomerular hypertrophy, and mesangial matrix expansion, whereas SR-A-knockout mice showed reduced glomerular size and mesangial matrix area. In these diabetic SR-A-knockout mice, the number of macrophages that infiltrated into glomeruli was remarkably reduced (P < 0.05), suggesting that SR-A-dependent glomerular migration of macrophages plays an important role in the pathogenesis of diabetic nephropathy. In terms of CD36, incubation of glycolaldehyde-modified bovine serum albumin (GA-BSA) with 3T3-L1 adipocytes reduced leptin secretion by these cells. The binding of GA-BSA to these cells and subsequent endocytic degradation were effectively inhibited by a neutralizing anti-CD36 antibody. AGE-induced downregulation of leptin was protected by N-acetyl-cysteine, an antioxidant. These results indicate that the interaction of AGE ligands with 3T3-L1 adipocytes via CD36 induces oxidative stress and leads to inhibition of leptin expression by these cells, suggesting a potential link of this phenomenon to exacerbation of the insulin sensitivity in metabolic syndrome.
authors.affiliation: Department of Medical Biochemistry, Kumamoto University Graduate School of Medical and Pharmaceutical Sciences, Honjo 1-1-1, Kumamoto 860-8556, Japan. horiuchi@gpo.kumamoto-u.ac.jp
authors.forename: Seikoh
authors.initials: S
authors.lastname: Horiuchi
authors.forename: Yuka
authors.initials: Y
authors.lastname: Unno
authors.forename: Hitomi
authors.initials: H
authors.lastname: Usui
authors.forename: Kenichi
authors.initials: K
authors.lastname: Shikata
authors.forename: Kaori
authors.initials: K
authors.lastname: Takaki
authors.forename: Wakako
authors.initials: W
authors.lastname: Koito
authors.forename: Yu-Ichiro
authors.initials: Y
authors.lastname: Sakamoto
authors.forename: Ryoji
authors.initials: R
authors.lastname: Nagai
authors.forename: Kenji
authors.initials: K
authors.lastname: Makino
authors.forename: Akira
authors.initials: A
authors.lastname: Sasao
authors.forename: Jun
authors.initials: J
authors.lastname: Wada
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000502:physiology; D000818:Animals; D018955:CD36 Antigens / Q000502:physiology*; D003928:Diabetic Nephropathies / Q000517:prevention & control; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D020738:Leptin / Q000037:antagonists & inhibitors / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000502:physiology*; D018077:Receptors, Leukotriene / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D018955:CD36 Antigens; D017127:Glycation End Products, Advanced; D020738:Leptin; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene