title: Deletion of scavenger receptor A protects mice from progressive nephropathy independent of lipid control during diet-induced hyperlipidemia.
abstract: Scavenger receptor A (SR-A) is a key transmembrane receptor in the endocytosis of lipids and contributes to the pathogenesis of atherosclerosis. To assess its role in hyperlipidemic chronic kidney disease, wild-type and SR-A-deficient (knockout) mice underwent uninephrectomy followed by either normal or high-fat diet. After 16 weeks of diet intervention, hyperlipidemic wild-type mice presented characteristic features of progressive nephropathy: albuminuria, renal fibrosis, and overexpression of transforming growth factor (TGF)-β1/Smad. These changes were markedly diminished in hyperlipidemic knockout mice and attributed to reduced renal lipid retention, oxidative stress, and CD11c(+) cell infiltration. In vitro, overexpression of SR-A augmented monocyte chemoattractant protein-1 release and TGF-β1/Smad activation in HK-2 cells exposed to oxidized low-density lipoprotein. SR-A knockdown prevented lipid-induced cell injury. Moreover, wild-type to knockout bone marrow transplantation resulted in renal fibrosis in uninephrectomized mice following 16 weeks of the high-fat diet. In contrast, knockout to wild-type bone marrow transplantation led to markedly reduced albuminuria, CD11c(+) cell infiltration, and renal fibrosis compared to wild-type to SR-A knockout or wild-type to wild-type bone marrow transplanted mice, without difference in plasma lipid levels. Thus, SR-A on circulating leukocytes rather than resident renal cells predominantly mediates lipid-induced kidney injury.
authors.affiliation: Division of Nephrology, Guangdong General Hospital, Guangzhou, China.
authors.forename: Wenjian
authors.initials: W
authors.lastname: Wang
authors.affiliation: Division of Nephrology, Guangdong General Hospital, Guangzhou, China.
authors.forename: Bin
authors.initials: B
authors.lastname: He
authors.affiliation: Division of Nephrology, Guangdong General Hospital, Guangzhou, China. Electronic address: weishi_gz@126.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: Division of Nephrology, Guangdong General Hospital, Guangzhou, China.
authors.forename: Xinling
authors.initials: X
authors.lastname: Liang
authors.affiliation: Division of Nephrology, Guangdong General Hospital, Guangzhou, China.
authors.forename: Jianchao
authors.initials: J
authors.lastname: Ma
authors.affiliation: Division of Nephrology, Guangdong General Hospital, Guangzhou, China.
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Shan
authors.affiliation: Division of Nephrology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Zhaoyong
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Division of Nephrology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Farhad R
authors.initials: FR
authors.lastname: Danesh
mesh_terms: D000419:Albuminuria / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D016026:Bone Marrow Transplantation; D039521:CD11c Antigen / Q000378:metabolism; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism; D002908:Chronic Disease; D004041:Dietary Fats / Q000097:blood / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D005355:Fibrosis; D006949:Hyperlipidemias / Q000150:complications* / Q000209:etiology; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009392:Nephrectomy; D018384:Oxidative Stress; D034622:RNA Interference; D051117:Scavenger Receptors, Class A / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: C111835:CCL2 protein, human; D039521:CD11c Antigen; D018932:Chemokine CCL2; D004041:Dietary Fats; C495139:MSR1 protein, human; C495140:Msr1 protein, mouse; D051117:Scavenger Receptors, Class A; D051785:Smad Proteins; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D013482:Superoxide Dismutase