title: Macrophage scavenger receptor-a-deficient mice are resistant against diabetic nephropathy through amelioration of microinflammation.
abstract: Microinflammation is a common major mechanism in the pathogenesis of diabetic vascular complications, including diabetic nephropathy. Macrophage scavenger receptor-A (SR-A) is a multifunctional receptor expressed on macrophages. This study aimed to determine the role of SR-A in diabetic nephropathy using SR-A-deficient (SR-A(-/-)) mice. Diabetes was induced in SR-A(-/-) and wild-type (SR-A(+/+)) mice by streptozotocin injection. Diabetic SR-A(+/+) mice presented characteristic features of diabetic nephropathy: albuminuria, glomerular hypertrophy, mesangial matrix expansion, and overexpression of transforming growth factor-beta at 6 months after induction of diabetes. These changes were markedly diminished in diabetic SR-A(-/-) mice, without differences in blood glucose and blood pressure levels. Interestingly, macrophage infiltration in the kidneys was dramatically decreased in diabetic SR-A(-/-) mice compared with diabetic SR-A(+/+) mice. DNA microarray revealed that proinflammatory genes were overexpressed in renal cortex of diabetic SR-A(+/+) mice and suppressed in diabetic SR-A(-/-) mice. Moreover, anti-SR-A antibody blocked the attachment of monocytes to type IV collagen substratum but not to endothelial cells. Our results suggest that SR-A promotes macrophage migration into diabetic kidneys by accelerating the attachment to renal extracellular matrices. SR-A may be a key molecule for the inflammatory process in pathogenesis of diabetic nephropathy and a novel therapeutic target for diabetic vascular complications.
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
authors.forename: Hitomi Kataoka
authors.initials: HK
authors.lastname: Usui
authors.forename: Kenichi
authors.initials: K
authors.lastname: Shikata
authors.forename: Motofumi
authors.initials: M
authors.lastname: Sasaki
authors.forename: Shinichi
authors.initials: S
authors.lastname: Okada
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Matsuda
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Shikata
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ogawa
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kido
authors.forename: Ryo
authors.initials: R
authors.lastname: Nagase
authors.forename: Kosuke
authors.initials: K
authors.lastname: Yozai
authors.forename: Sakiko
authors.initials: S
authors.lastname: Ohga
authors.forename: Atsuhito
authors.initials: A
authors.lastname: Tone
authors.forename: Jun
authors.initials: J
authors.lastname: Wada
authors.forename: Motohiro
authors.initials: M
authors.lastname: Takeya
authors.forename: Masahiro
authors.initials: M
authors.lastname: Takeya
authors.forename: Seikoh
authors.initials: S
authors.lastname: Horiuchi
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D000419:Albuminuria; D000818:Animals; D024141:Collagen Type IV / Q000378:metabolism; D003404:Creatinine / Q000652:urine; D003921:Diabetes Mellitus, Experimental; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D017127:Glycation End Products, Advanced / Q000378:metabolism; D007249:Inflammation / Q000235:genetics*; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D053495:Osteopontin / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051117:Scavenger Receptors, Class A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013311:Streptozocin; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D024141:Collagen Type IV; D017127:Glycation End Products, Advanced; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D051117:Scavenger Receptors, Class A; D016212:Transforming Growth Factor beta; D053495:Osteopontin; D013311:Streptozocin; D003404:Creatinine