Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Arterioscler Thromb Vasc Biol. Author manuscript; available in PMC 2010 September 1.
Published in final edited form as:
PMCID: PMC2748735

Renal Dysfunction Potentiates Foam Cell Formation by Repressing ABCA1

Yiqin Zuo, M.D., Ph.D.,1,4 Patricia Yancey, Ph.D.,2 Iris Castro, Ph.D.,5 Wasif Khan, Ph.D.,5 Masaru Motojima, Ph.D.,1 Iekuni Ichikawa, M.D., Ph.D.,1 Agnes B. Fogo, M.D.,1,2,4 MacRae F. Linton, M.D.,2,3 Sergio Fazio, M.D.,2,4 and Valentina Kon, M.D.1



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-κB). Treatment with the angiotensin receptor blocker (ARB) losartan decreased NF-κB and restored cholesterol efflux.


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

Keywords: Renal impairment, atherosclerosis, macrophage, ATP-binding cassette transporter A1, angiotensin

Patients with chronic kidney disease (CKD), including those with mild renal dysfunction, have very high risk for cardiovascular disease (CVD) (1-3). Our limited understanding of the underlying mechanisms of CKD-driven vasculopathy constrains development of specific therapeutic approaches. While risk reductions, through current therapeutic interventions, have halved the overall CVD morbidity and mortality in the general population (4), poor CV outcomes continue to escalate in CKD patients (1). Further confounding this issue is variability in the response of CKD patients to therapeutic interventions on lipids. Although lipid-lowering agents prevent CV events in patients with mild to moderate CKD (5-10), their effectiveness appears more equivocal as renal damage progresses to end stage renal disease (5,11,12). These observations suggest that renal dysfunction may exert a unique influence over the process of atherogenesis, and may influence response to standard lipid therapy.

Although renal damage can cause dyslipidemia, the increased incidence of CVD in CKD cannot be attributed to higher serum cholesterol per se (13). Recent studies indicate that multiple local vascular perturbations influence cholesterol trafficking and foam cell formation, a key process in atherogenesis (14-16). There is currently little information about foam cell formation in the setting of renal dysfunction. The formation of macrophage foam cells reflects a failure of cholesterol export mechanisms to keep pace with internalization of cholesterol from lipoproteins and cellular debris (14). Thus, macrophage cholesterol homeostasis is critically dependent on lipid efflux, which involves mobilization of excess cholesterol from intracellular pools to the plasma membrane and transfer to suitable external cholesterol acceptors (14-16). The key pathway for cholesterol movement out of macrophages involves an energy-dependent efflux linked to the ATP-binding cassette transporter A1 (ABCA1) (16,17). However, little is known about the status and regulation of this critical pathway in CKD.

Although we previously showed that renal impairment induced by uninephrectomy (UNx) in apoE-/- mice dramatically amplifies atherogenesis that was responsive to inhibition of angiotensin II actions, the underlying mechanism remained unclear (18). Notably, unlike other atherosclerosis-inducing conditions such as diabetes (19,20), where specific metabolites (i.e., glucose or advanced glycation end products) can influence macrophage lipid homeostasis in vitro, renal impairment does not have such a specific metabolite. We therefore used in vivo as well as ex vivo approaches to study the effects on macrophage lipid homeostasis in this model (11,21). Since angiotensin II (AII) inhibition is a mainstay in treatment of atherosclerotic heart disease (22,23) and CKD is an AII-responsive state (24) we also evaluated the effects of AII inhibition on macrophage lipid homeostasis and regulation of the efflux pathway in this setting.


For a detailed description please see the supplemental materials (available online at

Animals and Experimental Design

Female apoE-/- or wild type (WT) mice on C57BL/6 background (Jackson Laboratories) were maintained on normal mouse chow. Animal care and procedures were carried out in accordance with National Institutes of Health and Vanderbilt University animal care facility guidelines. At 9 weeks of age, apoE-/- and WT mice underwent uninephrectomy (UNx) or sham operation performed under isoflurane inhalation anesthesia. After one week, UNx and sham mice were begun on HFD (19,20,25) or continued on the regular chow and assigned to groups as follows: apoE-/- sham with no further treatment (sham on chow, n=10 or sham+HFD, n=5); apoE-/- UNx with no treatment (UNx on chow, n=15 or UNx+HFD, n=6); apoE-/- UNx treated with angiotensin receptor blocker (ARB, losartan, 100 mg/L in drinking water) (UNx on chow+L, n=11 or UNx+HFD+L, n=6) and WT sham on chow (WT sham, n=4) or WT UNx on chow (WT UNx, n=8). All mice were sacrificed at 18 weeks and serum cholesterol and triglyceride levels determined and peritoneal macrophages harvested as described (19,21,25).

Macrophage Cholesterol Content and Cholesterol Efflux

At termination of the study, total cholesterol (TC) and free cholesterol (FC) content was assessed in freshly isolated peritoneal macrophages, harvested by peritoneal lavage 3 days after peritoneal injection of 3% thioglycollate. Cells from each mouse were seeded and after 4 hour incubation, baseline cholesterol mass determined by gas-liquid chromatography (GLC) (18,26-28). Esterified cholesterol mass, cholesteryl ester (CE), was taken as the difference between total and free cholesterol. Cellular protein was assayed using the Lowry procedure and bovine serum albumin as a standard. For efflux studies, macrophages from mice in each group were pooled, washed, incubated for 24hr with each of the following: apoAI at 20μg/ml in DMEM, HDL at 150μg/ml in DMEM or DMEM alone. Cholesterol efflux was determined as the difference between cells incubated with DMEM alone and DMEM with one of cholesterol acceptors, apoAI or HDL, and expressed as the percent decrease in cell cholesterol (19,20,27-29).


Macrophage Cholesterol Content

Uninephrectomy in high-fat fed apoE-/- mice caused a dramatic expansion in macrophage cholesterol, including a 2.5-fold increase in total cholesterol (TC), a 1.8-fold increase in free cholesterol (FC) and a 3.0-fold increase in cholesterol ester (CE) (Table). Treatment with losartan reduced cellular cholesterol by 76%. The cellular cholesterol differences were not directly explained by serum lipid levels (Table). To evaluate whether reduction in renal mass affects cellular cholesterol in the absence of in vivo cholesterol loading, we also assessed the cellular lipid characteristics in macrophages of apoE-/- mice with UNx or sham operation maintained on regular chow diet. ApoE-/- UNx mice on chow also showed a marked increase (3-fold) in macrophage cholesterol, reflecting largely an increase in FC (Table). Again, the cellular cholesterol differences in UNx vs. sham on chow were not explained by serum lipid levels (Table). ARB treatment significantly reduced cellular TC, FC and CE (Table), in the absence of any reduction in serum cholesterol.

Serum Lipids and Macrophage Cholesterol Content

Macrophage Cholesterol Efflux

Uninephrectomy resulted in blunted macrophage cholesterol efflux, regardless of diet. In the presence of apolipoprotein AI (apoAI) as an extracellular cholesterol acceptor, cellular cholesterol levels in macrophages from apoE-/- UNx+HFD remained elevated compared to cells harvested from apoE-/- sham+HFD (Figure 1A) due to strikingly repressed efflux (5.4±0.9% in UNx+HFD versus 31.6±3.5 in sham+HFD, p<0.05). ARB treatment in these UNx mice partially restored efflux (to 16.1±2.1%, p<0.05 vs. UNx+HFD). Similarly, repressed efflux was seen in macrophage of UNx maintained on chow, (UNx, 7.9±2.7% vs. sham, 17.7±2.9; p<0.05) (Figure 1B). In vivo treatment of apoE-/- UNx mice with losartan also significantly restored efflux, (to 12.0±2.1%, p<0.05 vs. UNx). Similar trends were observed when the macrophages were incubated with HDL as cholesterol acceptor, but the differences did not reach statistical significance (data not shown).

Figure 1
Uninephrectomy blunts macrophage cholesterol efflux which is restored by losartan. (A) Efflux from macrophage of apoE-/- on HFD with sham operation (sham, n=5), uninephrectomy (UNx, n=6) or UNx+losartan (UNx+L, n=6). (B) apoE-/- on chow with sham (n=6), ...

Macrophage ATP-binding Cassette Transporter (ABC) A1 and ABCG1

To elucidate mechanisms for the reduced cholesterol efflux in macrophages of UNx mice, we examined the expression of pivotal transporters involved in cholesterol efflux. As noted above, regardless of diet, UNx increased cellular cholesterol level which is expected to increase ABCA1 expression (30). Notably, however, the increase is stunted. Thus, although the level of cellular cholesterol in UNx on chow is similar to that seen in mice with intact kidneys on HFD, the level of ABCA1 expression is strikingly less in macrophages from UNx mice (Table and Figure 3). Greater cellular cholesterol loading with HFD feeding further emphasizes this point as comparison of UNx on HFD had dramatically lower level of ABCA1 expression than shams on HFD. Notably, increased efflux with ARB was linked to increased macrophage ABCA1 levels (Figure 2). By contrast, ABCG1 protein levels were not affected by ARB in apoE-/- sham vs UNx (ABCG1/β actin ratio 0.14±0.02 in sham vs 0.14±0.01 in UNx and 0.26±0.06 in UNx+L, p=NS among the groups).

Figure 2
Uninephrectomy depresses macrophage ABCA1 expression which is restored by losartan. (A) Western blot of ABCA1/β-actin in macrophages of apoE-/- sham on chow, sham+HFD, UNx+chow, UNx+HFD. B) Semi-quantitative data of ABCA1. Sham on chow (n=6), ...
Figure 3
Uninephrectomy stunts macrophage ABCA1 expression. Macrophage cholesterol content versus ABCA1 expression assessed in macrophages from apoE-/- groups of sham on normal chow, sham+HFD, UNx on chow, and UNx+HFD groups.

To further evaluate the mechanisms by which UNx modulates the level of abundance of the transporters, we evaluated mRNA expression. ABCA1 gene expression in apoE-/- UNx on chow was significantly lower when compared with apoE-/- sham-operated mice on chow (by 36%, p<0.05). Examination of degradation of ABCA1 protein revealed numerically more degradation of ABCA1 in UNx compared with ABCA1 in shams (47%±5% in macrophages from UNx versus 30%±9% in macrophages from shams, p=NS). ABCA1 degradation was determined as the difference between ABCA1 protein before and after addition of the protease inhibitor, ALLN (-8%±9% in macrophages from UNx versus 28%±34% in macrophages from shams, p=NS). Notably, even in non-hyperlipidemic wild types mice (WT), ABCA1 mRNA expression was also lower in UNx than in sham-operated WT (by 38%, p<0.05).

Macrophage NF-κB

The NF-κB pathway is involved in the downregulation of ABCA1 in cholesterol-loaded cells (30,31), and can be activated in renal disease (32). We found significantly increased macrophage nuclear NF-kB activity assessed by electrophoretic mobility-shift assay (EMSA) in apoE-/- UNx versus apoE-/- sham macrophages, with almost two-fold increase in the protein levels of RelA and p50 DNA binding subunits of NF-kB (p<0.05 UNx vs. sham) (Figure 4A and B). Ex vivo exposure of UNx macrophages to an NF-κB antagonist, ammonium pyrrolidinedithiocarbamate (PDTC), significantly increased ABCA1 protein levels (Figure 4C). The up-regulation of both p65 and p50 NF-κB subunits (Figure 4B) was inhibited by treatment with ARB. Taken together, these data suggest that UNx suppresses ABCA1 through activation of NF-κB, and that ARB restores ABCA1 by decreasing activation of NF-κB.

Figure 4
Uninephrectomy increases macrophage NF-κB which can be lessened by losartan, while antagonism of NF-κB restores ABCA1 expression. (A) Electrophoretic mobility-shift assay (EMSA) of NF-κB activity in macrophages sham (n=5) and UNx ...


The present study makes the novel observation that in vivo, renal impairment induced by reduction in renal mass markedly increases macrophage lipid content. We further show that the mechanisms for this involve reduction in cholesterol efflux from the macrophages. The underlying molecular mechanism involves decreased macrophage ABCA1 transporter and activated NF-κB. Antagonizing activated macrophage NF-κB with ARB or a specific NF-κB inhibitor reversed these events. These data indicate that the dramatic acceleration in atherosclerosis observed in the setting of renal dysfunction may be related to abnormal macrophage cholesterol homeostasis due, at least in part, to repression of ABCA1 caused by activated NF-κB, which can be ameliorated by a novel effect of ARB treatment.

Since foam cell formation depends on perturbations in macrophage cholesterol homeostasis, we investigated whether renal dysfunction affects macrophage lipid metabolism in this setting. We show that uninephrectomy in apoE-/-mice on high fat Western diet causes significant accumulation of macrophage cholesterol, compared with mice with intact kidneys. The cellular lipid expansion was not simply a reflection of the in vivo plasma lipid environment, as the plasma cholesterol in UNx was only 30% higher than sham while the macrophage cholesterol in UNx was increased by 250% (Table). A similar step-up between plasma and cellular cholesterol was seen in UNx versus shams with intact kidneys maintained on regular chow. These data indicate that foam cell formation and atherosclerosis do not necessarily parallel plasma lipid levels, particularly in the presence of renal dysfunction (5, 33-35).

Our studies further show that in vivo treatment with an ARB, losartan, reduced the cholesterol content in macrophages of UNx mice on either diet. Epidemiological studies have documented fewer cardiovascular events and increased survival with ARB in the general population, and in patients with early renal damage (22, 36). The benefits of ARB in various studies have occurred in the absence of any plasma lipid-lowering effects and have previously been ascribed to modulation of macrophage infiltration, endothelial cell activation, or vascular oxidant stress (18, 37). We now show that ARB directly modulates macrophage cholesterol handling, thereby providing a mechanism for our previous observation (18). In this previous study with the UNx model, we showed that ARB treatment lessened atherosclerosis while decreasing blood pressure, whereas a non-specific vasodilator (hydralazine) reduced blood pressure without affecting atherosclerosis. This suggests that the vascular effects of an ARB are not dependent on systemic hemodynamics (18). Nonetheless, in the current study we cannot exclude possible hemodynamic effects on macrophage cholesterol accumulation.

Patients with renal damage have increased activity of scavenger receptors, which promote increased cellular uptake of cholesterol, however, once upregulated, macrophages do not down-regulate scavenger receptors or inflow of cholesterol by this pathway (38). Cholesterol efflux in this setting is therefore a pivotal step in determining whether intracellular lipid homeostasis is maintained or whether the macrophage will turn into a foam cell (39). Our data show that a modest reduction in renal mass decreases macrophage cholesterol efflux. This effect is linked to repression of the macrophage ABCA1 transporter (Figure 3). UNx also reduced ABCA1 gene expression in normolipemic wild type mice. This effect is also apparent in humans, in that plasma from CKD patients downregulates ABCA1 in cultured endothelial cells (40). Our study makes the novel observation that repression of the ABCA1 transporter underlies the decreased efflux and expanded cholesterol content in macrophages in renal dysfunction. UNx did not significantly change ABCG1 levels despite its established effects on cholesterol efflux. These findings reiterate the knowledge that changes in ABCA1 vs ABCG1 are not necessarily coordinated in a parallel fashion (19, 29, 41). Our studies also show that in vivo treatment with ARB restored macrophage ABCA1 expression in renal dysfunction. While ARB increased macrophage ABCA1 expression, macrophage cholesterol efflux was not completely normalized. These results suggest possible involvement of other mechanisms, including oxidative stress or perturbation in intracellular lipid trafficking. However, in cultured human macrophages exposed to the ARB telmisartan cholesterol efflux was increased via PPARγ-dependent pathway together with upregulation of ABCA1, suggesting a direct ARB effect on macrophages (42). These results complement previous in vivo and in vitro findings that exogenous AII downregulates ABCA1 (29, 42, 43). Taken together, these observations suggest a pivotal importance of the AII-ABCA1 interaction for macrophage cholesterol homeostasis in the setting of renal dysfunction, providing a basis for possible modulation of excess CVD risk in this setting.

We then explored potential mechanisms of interactions between AII and ABCA1. ABCA1 is markedly upregulated by oxysterols via activation of liver X receptor (LXR) (44), and is downregulated by inflammatory stimuli, including lipopolysaccharide and interleukin-1β through the NF-κB signaling pathway (30, 31, 45). The relationship between the NF-κB system, ABCA1, AII and lipid accumulation in the setting of renal damage remains unclear. We show that UNx macrophages have significantly elevated NF-κB activity (Figure 4) together with a corresponding increase in protein expression of NF-κB DNA binding subunits, p65 (RelA) and p50 (Figure 4A and B). We also show that specific antagonism of the NF-κB activation pathway in macrophages lessens the repression of the ABCA1 transporter (Figure 4C). Further, ARB significantly decreased up-regulation of RelA and p50, suggesting this as a potential key regulatory step (Figure 4B) (46).

In summary, our study shows for the first time that loss of the renal parenchyma disrupts macrophage cholesterol homeostasis by repressing ABCA1 through activation of the NF-κB pathway. Further, ARB downregulates NF-κB subunits, upregulates ABCA1 and thus lessens macrophage cholesterol burden. These advantageous effects of ARB may decrease atherogenesis and provide further support for the use of ARB to decrease CV risk in CKD patients.

Supplementary Material


The authors acknowledge the expert technical assistance of Cathy Xu.

Sources of Funding This work was supported in part by grants from NIH DK44757 and HL087061 (V.K.), DK37868 (I.I.), HL53989 and HL65405 (M.F.L), HL65709 and 57986 (S.F.), and the Lipid, Lipoprotein and Atherosclerosis Core of the Vanderbilt Mouse Metabolic Phenotyping Center (NIH DK59637-01).


Disclosures None.


1. Weiner DE, Tabatabai S, Tighiouart H, Elsayed E, Bansal N, Griffith J, Salem DN, Levey AS, Sarnak MJ. Cardiovascular outcomes and all-cause mortality: exploring the interaction between CKD and cardiovascular disease. Am J Kidney Dis. 2006;48(3):392–401. [PubMed]
2. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296–1305. [PubMed]
3. Anavekar NS, McMurray JJ, Velazquez EJ, Solomon SD, Kober L, Rouleau JL, White HD, Nordlander R, Maggioni A, Dickstein K, Zelenkofske S, Leimberger JD, Califf RM, Pfeffer MA. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med. 2004;351:1285–1295. [PubMed]
4. Ford ES, Ajani UA, Croft JB, Critchley JA, Phil D, Labarthe DR, Kottke TE, Giles WH, Capewell S. Explaining the decrease in U.S. deaths from coronary disease, 1980-2000. N Engl J Med. 2007;356:2388–2398. [PubMed]
5. Wanner C, Krane V, März W, Olschewski M, Mann JF, Ruf G, Ritz E. German Diabetes and Dialysis Study Investigators. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med. 2005;353:238–248. [PubMed]
6. Collins R, Armitage J, Parish S, Sleigh P, Peto R. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003;361:2005–2016. [PubMed]
7. Tonelli M, Collins D, Robins S, Bloomfield H, Curhan GC. Veterans’ Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) Investigators. Gemfibrozil for secondary prevention of cardiovascular events in mild to moderate chronic renal insufficiency. Kidney Int. 2004;66:1123–11230. [PubMed]
8. Tonelli M, Isles C, Craven T, Tonkin A, Pfeffer MA, Shepherd J, Sacks FM, Furberg C, Cobbe SM, Simes J, West M, Packard C, Curhan GC. Effect of pravastatin on rate of kidney function loss in people with or at risk for coronary disease. Circulation. 2005;112:171–178. [PubMed]
9. Asselbergs FW, Diercks GF, Hillege HL, van Boven AJ, Janssen WM, Voors AA, de Zeeuw D, de Jong PE, van Veldhuisen DJ, van Gilst WH. Prevention of Renal and Vascular Endstage Disease Intervention Trial (PREVEND IT) Investigators. Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation. 2004;110:2809–2816. [PubMed]
10. Shepherd J, Kastelein JP, Bittner VA, Carmena R, Deedwania PC, Breazna A, Dobson S, Wilson DJ, Zuckerman AL, Wenger NK. Treating to New Targets Steering Committee and Investigators. Intensive lipid lowering with atorvastatin in patients with coronary artery disease, diabetes, and chronic kidney disease. Mayo Clin Proc. 2008;83:870–879. [PubMed]
11. Andreucci VE, Fissell RB, Bragg-Gresham JL, Ethier J, Greenwood R, Pauly M, Wizemann V, Port FK. Dialysis Outcomes and Practice Patterns Study (DOPPS) data on medications in hemodialysis patients. Am J Kidney Dis. 2004;44:61–67. [PubMed]
12. Lahoz C, Mostaza JM, Mantilla MT, Taboada M, Tranche S, López-Rodriguez I, Monteiro B, Soler B, Sanchez-Zamorano MA, Martin-Jadraque R. Achievement of therapeutic goals and utilization of evidence-based cardiovascular therapies in coronary heart disease patients with chronic kidney disease. Am J Cardiol. 2008;101:1098–1102. [PubMed]
13. Vaziri ND. Dyslipidemia of chronic renal failure: the nature, mechanisms, and potential consequences. Am J Physiol Renal Physiol. 2006;290:F262–272. [PubMed]
14. Jessup W, Gelissen IC, Gaus K, Kritharides L. Roles of ATP binding cassette transporters A1 and G1, scavenger receptor BI and membrane lipid domains in cholesterol export from macrophages. Curr Opin Lipido. 2006;17:247–257. [PubMed]
15. Yancey PG, Bortnick AE, Kellner-Weibel G, de la Llera-Moya M, Phillips MC, Rothblat GH. Importance of different pathways of cellular cholesterol efflux. Arterioscler Thromb Vasc Biol. 2003;23:712–719. [PubMed]
16. Joyce CW, Amar MJ, Lambert G, Vaisman BL, Paigen B, Najib-Fruchart J, Hoyt RF, Jr, Neufeld ED, Remaley AT, Fredrickson DS, Brewer HB, Jr, Santamarina-Fojo S. The ATP binding cassette transporter A1 (ABCA1) modulates the development of aortic atherosclerosis in C57BL/6 and apoE-knockout mice. Proc Natl Acad Sci U S A. 2002;99:407–412. [PubMed]
17. Brooks-Wilson A, Marcil M, Clee SM, Zhang LH, Roomp K, van Dam M, Yu L, Brewer C, Collins JA, Molhuizen HO, Loubser O, Ouelette BF, Fichter K, Ashbourne-Excoffon KJ, Sensen CW, Scherer S, Mott S, Denis M, Martindale D, Frohlich J, Morgan K, Koop B, Pimstone S, Kastelein JJ, Genest J, Jr, Hayden MR. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet. 1999;22:336–345. [PubMed]
18. Suganuma E, Zuo Y, Ayabe N, Ma J, Babaev VR, Linton MF, Fazio S, Ichikawa I, Fogo AB, Kon V. Antiatherogenic effects of angiotensin receptor antagonism in mild renal dysfunction. J Am Soc Nephrol. 2006;17:433–441. [PubMed]
19. Mauldin JP, Srinivasan S, Mulya A, Gebre A, Parks JS, Daugherty A, Hedrick CC. Reduction in ABCG1 in Type 2 diabetic mice increases macrophage foam cell formation. J Biol Chem. 2006;281:21216–21224. [PubMed]
20. Li AC, Binder CJ, Gutierrez A, Brown KK, Plotkin CR, Pattison JW, Valledor AF, Davis RA, Willson TM, Witztum JL, Palinski W, Glass CK. Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha, beta/delta, and gamma. J Clin Invest. 2004;14:1564–1576. [PMC free article] [PubMed]
21. Bro S, Bentzon JF, Falk E, Andersen CB, Olgaard K, Nielsen LB. Chronic renal failure accelerates atherogenesis in apolipoprotein E-deficient mice. J Am Soc Nephrol. 2003;14:2466–2474. [PubMed]
22. ONTARGET Investigators. Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, Dagenais G, Sleight P, Anderson C. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358:1547–1559. [PubMed]
23. The Heart Outcomes Prevention Evaluation Study Investigator. Effects of an angiotensin-converting–enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145–153. [PubMed]
24. Toto R, Palmer BF. Rationale for combination angiotensin receptor blocker and angiotensin-converting enzyme inhibitor treatment and end-organ protection in patients with chronic kidney disease. Am J Nephrol. 2008;28:372–380. [PubMed]
25. Babaev VR, Yancey PG, Ryzhov SV, Kon V, Breyer MD, Magnuson MA, Fazio S, Linton MF. Conditional knockout of macrophage PPARgamma increases atherosclerosis in C57BL/6 and low-density lipoprotein receptor-deficient mice. Arterioscler Thromb Vasc Biol. 2005;25:1647–1653. [PubMed]
26. Kaplan M, Aviram M, Knopf C, Keidar S. Angiotensin II reduces macrophage cholesterol efflux: a role for the AT-1 receptor but not for the ABC1 transporter. Biochem Biophys Res Commun. 2002;290:1529–1534. [PubMed]
27. Yancey PG, Kawashiri MA, Moore R, Glick JM, Williams DL, Connelly MA, Rader DJ, Rothblat GH. In vivo modulation of HDL phospholipid has opposing effects on SR-BI- and ABCA1-mediated cholesterol efflux. J Lipid Res. 2004;45:337–346. [PubMed]
28. Terasaka N, Wang N, Yvan-Charvet L, Tall AR. High-density lipoprotein protects macrophages from oxidized low-density lipoprotein-induced apoptosis by promoting efflux of 7-ketocholesterol via ABCG1. Proc Natl Acad Sci U S A. 2007;104:15093–15098. [PubMed]
29. Wang Y, Chen Z, Liao Y, Mei C, Peng H, Wang M, Guo H, Lu H. Angiotensin II increases the cholesterol content of foam cells via down-regulating the expression of ATP-binding cassette transporter A1. Biochem Biophys Res Commun. 2007;353:650–654. [PubMed]
30. Chen M, Li W, Wang N, Zhu Y, Wang X. ROS and NF-kappaB but not LXR mediate IL-1beta signaling for the downregulation of ATP-binding cassette transporter A1. Am J Physiol Cell Physiol. 2007;292:C1493–1501. [PubMed]
31. Baranova I, Vishnyakova T, Bocharov A, Chen Z, Remaley AT, Stonik J, Eggerman TL, Patterson AP. Lipopolysaccharide down regulates both scavenger receptor B1 and ATP binding cassette transporter A1 in RAW cells. Infect Immun. 2002;70:2995–3003. [PMC free article] [PubMed]
32. Li XC, Zhuo JL. Nuclear factor-kappaB as a hormonal intracellular signaling molecule: focus on angiotensin II-induced cardiovascular and renal injury. Curr Opin Nephrol Hypertens. 2008;17:37–43. [PMC free article] [PubMed]
33. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM. Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495–1504. [PubMed]
34. Tonelli M, Keech A, Shepherd J, Sacks F, Tonkin A, Packard C, Pfeffer M, Simes J, Isles C, Furberg C, West M, Craven T, Curhan G. Effect of pravastatin in people with diabetes and chronic kidney disease. J Am Soc Nephrol. 2005;16:3748–3754. [PubMed]
35. Fathi R, Isbel N, Short L, Haluska B, Johnson D, Marwick TH. The effect of long-term aggressive lipid lowering on ischemic and atherosclerotic burden in patients with chronic kidney disease. Am J Kidney Dis. 2004;43:45–52. [PubMed]
36. Mann JF, Lonn EM, Yi Q, Gerstein HC, Hoogwerf BJ, Pogue J, Bosch J, Dagenais GR, Yusuf S. HOPE Investigators. Effects of vitamin E on cardiovascular outcomes in people with mild-to-moderate renal insufficiency: results of the HOPE study. Kidney Int. 2004;65:1375–1380. [PubMed]
37. Dandona P, Dhindsa S, Ghanim H, Chaudhuri A. Angiotensin II and inflammation: the effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockade. J Hum Hypertens. 2007;21:20–27. [PubMed]
38. Chmielewski M, Bryl E, Marzec L, Aleksandrowicz E, Witkowski JM, Rutkowski B. Expression of scavenger receptor CD36 in chronic renal failure patients. Artif Organs. 2005;29:608–614. [PubMed]
39. Tall AR, Costet P, Wang N. Regulation and mechanisms of macrophage cholesterol efflux. J Clin Invest. 2002;110:899–904. [PMC free article] [PubMed]
40. Cardinal H, Raymond MA, Hebert MJ, Madore F. Uraemic plasma decreases the expression of ABCA1, ABCG1 and cell-cycle genes in human coronary arterial endothelial cells. Nephrol Dial Transplant. 2007;22:409–416. [PubMed]
41. Delvecchio CJ, Bilan P, Nair P, Capone JP. LXR-induced reverse cholesterol transport in human airway smooth muscle is mediated exclusively by ABCA1. Am J Physiol Lung Cell Mol Physiol. 2008;295:L949–L957. [PubMed]
42. Nakaya K, Ayaori M, Hisada T, Sawada S, Tanaka N, Iwamoto N, Ogura M, Yakushiji E, Kusuhara M, Nakamura H, Ohsuzu F. Telmisartan enhances cholesterol efflux from THP-1 macrophages by activating PPARgamma. J Atheroscler Thromb. 2007;14:133–141. [PubMed]
43. Takata Y, Chu V, Collins AR, Lyon CJ, Wang W, Blaschke F, Bruemmer D, Caglayan E, Daley W, Higaki J, Fishbein MC, Tangirala RK, Law RE, Hsueh WA. Transcriptional repression of ATP-binding cassette transporter A1 gene in macrophages: a novel atherosclerotic effect of angiotensin II. Circ Res. 2005;97:e88–e96. [PubMed]
44. Sparrow CP, Baffic J, Lam MH, Lund EG, Adams AD, Fu X, Hayes N, Jones AB, Macnaul KL, Ondeyka J, Singh S, Wang J, Zhou G, Moller DE, Wright SD, Menke JG. A potent synthetic LXR agonist is more effective than cholesterol loading at inducing ABCA1 mRNA and stimulating cholesterol efflux. J Biol Chem. 2002;277:10021–10027. [PubMed]
45. Ferreira V, van Dijk KW, Groen AK, Vos RM, van der Kaa J, Gijbels MJ, Havekes LM, Pannekoek H. Macrophage-specific inhibition of NF-kappaB activation reduces foam-cell formation. Atherosclerosis. 2007;192:283–290. [PubMed]
46. Yoshiyama M, Omura T, Takeuchi K, Kim S, Shimada K, Yamagishi H, Teragaki M, Akioka K, Iwao H, Yoshikawa J. Angiotensin blockade inhibits increased JNKs, AP-1 and NF- kappa B DNA-binding activities in myocardial infarcted rats. J Mol Cell Cardiol. 2001;33:799–810. [PubMed]