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

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

Medicine/Division of Cardiology, UCLA David Geffen School of Medicine, Los Angeles,, CA 90095-1679

Corresponding Author: 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 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 to C57BL/6J and LDLR-/- mice on chow (p<0.001 and p<0.001, respectively) and compared to 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.

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