Renal dysfunction potentiates foam cell formation by repressing ABCA1.

Zuo Y, Yancey P, Castro I, Khan WN, Khan W, Motojima M, Ichikawa I, Fogo AB, Linton MF, Fazio S, Kon V
Arterioscler Thromb Vasc Biol. 2009 29 (9): 1277-82

PMID: 19667109 · PMCID: PMC2748735 · DOI:10.1161/ATVBAHA.109.188995

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-kappaB). Treatment with the angiotensin receptor blocker (ARB) losartan decreased NF-kappaB 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-kappaB, and that ARB can restore cholesterol efflux.

MeSH Terms (19)

Angiotensin II Type 1 Receptor Blockers Animals Apolipoproteins E Atherosclerosis ATP-Binding Cassette Transporters ATP Binding Cassette Transporter 1 Cells, Cultured Cholesterol Disease Models, Animal Down-Regulation Female Foam Cells Kidney Diseases Losartan Mice Mice, Inbred C57BL Mice, Knockout Nephrectomy NF-kappa B

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