D-4F reduces EO6 immunoreactivity, SREBP-1c mRNA levels, and renal inflammation in LDL receptor-null mice fed a Western diet.
LDL receptor-null (LDLR(-/-)) mice on a Western diet (WD) develop endothelial dysfunction and atherosclerosis, which are improved by the apolipoprotein A-I (apoA-I) mimetic peptide D-4F. Focusing on the kidney, LDLR(-/-)mice were fed a WD with D-4F or the inactive control peptide scrambled D-4F (ScD-4F) added to their drinking water. The control mice (ScD-4F) developed glomerular changes, increased immunostaining for MCP-1/CCL2 chemokine, increased macrophage CD68 and F4/80 antigens, and increased oxidized phospholipids recognized by the EO6 monoclonal antibody in both glomerular and tublo-interstitial areas. All of these parameters were significantly reduced by D-4F treatment, approaching levels found in wild-type C57BL/6J or LDLR(-/-) mice fed a chow diet. Sterol-regulatory element binding protein-1c (SREBP-1c) mRNA levels and triglyceride levels were elevated in the kidneys of the control mice (ScD-4F) fed the WD compared with C57BL/6J and LDLR(-/-) mice on chow (P < 0.001 and P < 0.001, respectively) and compared with D-4F-treated mice on the WD (P < 0.01). There was no significant difference in plasma lipids, lipoproteins, glucose, blood pressure, or renal apoB levels between D-4F- and ScD-4F-treated mice. We conclude that D-4F reduced renal oxidized phospholipids, resulting in lower expression of SREBP-1c, which, in turn, resulted in lower triglyceride content and reduced renal inflammation.
Buga
Georgette M
GM
Department of Medicine, David Geffen School of Medicine at the University of California-Los Angeles, Los Angeles, CA 90095-1679, USA. gbuga@mednet.ucla.edu
Frank
Joy S
JS
Mottino
Giuliano A
GA
Hakhamian
Ashkan
A
Narasimha
Ajay
A
Watson
Andrew D
AD
Yekta
Babak
B
Navab
Mohamad
M
Reddy
Srinivasa T
ST
Anantharamaiah
G M
GM
Fogelman
Alan M
AM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D016632:Apolipoprotein A-I / Q000008:administration & dosage / Q000494:pharmacology*; D004032:Diet; D005260:Female; D007249:Inflammation / Q000378:metabolism*; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D050356:Lipid Metabolism; D051379:Mice; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism
D000911:Antibodies, Monoclonal; D016632:Apolipoprotein A-I; C465468:D-4F peptide; D010743:Phospholipids; D012333:RNA, Messenger; D011973:Receptors, LDL; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides