title: Inflammatory stress exacerbates lipid-mediated renal injury in ApoE/CD36/SRA triple knockout mice.
abstract: Both lipids and inflammation play important roles in the progression of kidney disease. This study was designed to investigate whether inflammation exacerbates lipid accumulation via LDL receptors (LDLr), thereby causing renal injury in C57BL/6J mice, apolipoprotein E (ApoE) knockout (KO) mice, and ApoE/CD36/scavenger receptor A triple KO mice. The mice were given a subcutaneous casein injection to induce inflammatory stress. After 14 wk, terminal blood samples were taken for renal function, lipid profiles, amyloid A (SAA), and IL-6 assays. Lipid accumulation in kidneys was visualized by oil red O staining. Fibrogenic molecule expression in kidneys was examined. There was a significant increase in serum SAA and IL-6 in the all casein-injected mice compared with respective controls. Casein injection reduced serum total cholesterol, LDL cholesterol, and HDL cholesterol and caused lipid accumulation in kidneys from three types of mice. The expression of LDLr and its regulatory proteins sterol-responsive element-binding protein (SREBP) 2 and SREBP cleavage-activating protein (SCAP) were upregulated in inflamed mice compared with controls. Casein injection induced renal fibrosis accompanied by increased expression of fibrogenic molecules in the triple KO mice. These data imply that inflammation exacerbates lipid accumulation in the kidney by diverting lipid from the plasma to the kidney via the SCAP-SREBP2-LDLr pathway and causing renal injury. Low blood cholesterol levels, resulting from inflammation, may be associated with high risk for chronic renal fibrosis.
authors.affiliation: Centre for Lipid Research, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China.
authors.forename: Zhen E
authors.initials: ZE
authors.lastname: Xu
authors.forename: Yaxi
authors.initials: Y
authors.lastname: Chen
authors.forename: Ailong
authors.initials: A
authors.lastname: Huang
authors.forename: Zac
authors.initials: Z
authors.lastname: Varghese
authors.forename: John F
authors.initials: JF
authors.lastname: Moorhead
authors.forename: Feng
authors.initials: F
authors.lastname: Yan
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Powis
authors.forename: Qiu
authors.initials: Q
authors.lastname: Li
authors.forename: Xiong Z
authors.initials: XZ
authors.lastname: Ruan
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D018955:CD36 Antigens / Q000235:genetics; D002364:Caseins / Q000009:adverse effects; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D002908:Chronic Disease; D018450:Disease Progression; D005355:Fibrosis; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000097:blood; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D050356:Lipid Metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000378:metabolism; D051117:Scavenger Receptors, Class A / Q000235:genetics; D000685:Serum Amyloid A Protein / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D018955:CD36 Antigens; D002364:Caseins; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011973:Receptors, LDL; C102196:SREBP cleavage-activating protein; D051117:Scavenger Receptors, Class A; D000685:Serum Amyloid A Protein; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol