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Journal of Lipid Research, Vol. 49, 192-205, January 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

D-4F reduces EO6 immunoreactivity, SREBP-1c mRNA levels, and renal inflammation in LDL receptor-null mice fed a Western diet

Georgette M. Buga^1,*, Joy S. Frank^*, Giuliano A. Mottino^*, Ashkan Hakhamian^*, Ajay Narasimha, Andrew D. Watson^*, Babak Yekta^*, Mohamad Navab^*, Srinivasa T. Reddy^*,, G. M. Anantharamaiah and Alan M. Fogelman^*

^* Department of Medicine, David Geffen School of Medicine at the University of California–Los Angeles, Los Angeles, CA 90095-1679
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at the University of California–Los Angeles, Los Angeles, CA 90095-1679
The Atherosclerosis Research Unit, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294

Published, JLR Papers in Press, October 9, 2007.

¹ To whom correspondence should be addressed. e-mail: gbuga{at}mednet.ucla.edu

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.

Supplementary key words atherosclerosis • apolipoprotein A-I mimetic peptides • HDL • hyperlipidemia • kidney • lipoproteins • sterol-regulatory element binding protein-1

Abbreviations: eNOS, endothelial nitric oxide synthase; LDLR^–/–, LDL receptor-null; PAS, periodic acid-Schiff; ScD-4F, scrambled D-4F; SREBP-1c, sterol-regulatory element binding protein-1c; WD, Western diet

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