Renal dysfunction potentiates foam cell formation by repressing ABCA1.
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.


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.
Zuo
Yiqin
Y
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232-2584, USA.
Yancey
Patricia
P
Castro
Iris
I
Khan
Wasif N
WN
Khan
Wasif
W
Motojima
Masaru
M
Ichikawa
Iekuni
I
Fogo
Agnes B
AB
Linton
MacRae F
MF
Fazio
Sergio
S
Kon
Valentina
V
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism*; D007674:Kidney Diseases / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009392:Nephrectomy
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D047228:Angiotensin II Type 1 Receptor Blockers; D001057:Apolipoproteins E; D016328:NF-kappa B; D002784:Cholesterol; D019808:Losartan