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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1277.)
© 2009 American Heart Association, Inc.

National Cholesterol Awareness Month

Renal Dysfunction Potentiates Foam Cell Formation by Repressing ABCA1

Yiqin Zuo; Patricia Yancey; Iris Castro; Wasif Khan; Masaru Motojima; Iekuni Ichikawa; Agnes B. Fogo; MacRae F. Linton; Sergio Fazio; Valentina Kon

From the Departments of Pediatrics (Y.Z., M.M., I.I., A.B.F., V.K.), Medicine (P.Y., A.B.F., M.F.L., S.F.), Pharmacology (M.F.L.), Pathology (Y.Z., A.B.F., S.F.), and Microbiology and Immunology (I.C., W.K.), Vanderbilt University Medical Center, Nashville, Tenn.

Correspondence to Valentina Kon, MD, Vanderbilt University Medical Center, C-4204 Medical Center North, Nashville, TN 37232-2584. E-mail valentina.kon{at}vanderbilt.edu

Abstract

Objective— Patients with chronic kidney disease (CKD) have the highest risk for atherosclerotic cardiovascular disease (CVD). Current interventions have been insufficiently effective in lessening excess incidence and mortality from CVD in CKD patients versus other high-risk groups. The mechanisms underlying the heightened risk remain obscure but may relate to differences in CKD-induced atherogenesis, including perturbation of macrophage cholesterol trafficking.

Methods and Results— We examined the impact of renal dysfunction on macrophage cholesterol homeostasis in the apoE^–/– mouse model of atherosclerosis. Renal impairment induced by uninephrectomy dramatically increased macrophage cholesterol content, linked to striking impairment of macrophage cholesterol efflux. This blunted efflux was associated with downregulation of the cholesterol transporter ATP-binding cassette transporter A1 (ABCA1) and activation of the nuclear factor-kappa B (NF-B). Treatment with the angiotensin receptor blocker (ARB) losartan decreased NF-B and restored cholesterol efflux.

Conclusions— Our findings show that mild renal dysfunction perturbs macrophage lipid homeostasis by inhibiting cholesterol efflux, mediated by decreased ABCA1 transporter and activation of NF-B, and that ARB can restore cholesterol efflux.

Chronic kidney disease imparts tremendous risk for cardiovascular disease. We found that mild renal dysfunction induced by uninephrectomy dramatically increases macrophage cholesterol, blunts cholesterol efflux, downregulates cholesterol transporter ABCA1, and activates nuclear factor-kappa B. These effects are ameliorated by treatment with an angiotensin receptor blocker.

Key Words: renal impairment • atherosclerosis • macrophage • ATP-binding cassette transporter A1 • angiotensin