Macrophage scavenger receptor-a-deficient mice are resistant against diabetic nephropathy through amelioration of microinflammation.
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.
Usui
Hitomi Kataoka
HK
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.
Shikata
Kenichi
K
Sasaki
Motofumi
M
Okada
Shinichi
S
Matsuda
Mitsuhiro
M
Shikata
Yasushi
Y
Ogawa
Daisuke
D
Kido
Yuichi
Y
Nagase
Ryo
R
Yozai
Kosuke
K
Ohga
Sakiko
S
Tone
Atsuhito
A
Wada
Jun
J
Takeya
Motohiro
M
Takeya
Masahiro
M
Horiuchi
Seikoh
S
Kodama
Tatsuhiko
T
Makino
Hirofumi
H
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
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