Nrneph 2010 157
Nrneph 2010 157
Nrneph 2010 157
Introduction
more than 50% of deaths in patients with chronic kidney subsequent diapedesis into the intima.7 Chemokines
disease (CKD) on dialysis are attributable to cardio (chemotactic cytokines) and their receptors have been
vascular disease.1 even modest renal dysfunction, includ implicated in the migration of monocytes and t cells into
ing isolated albuminuria, results in a dramatic increase the arterial intima.8 the critical role for macrophages
in the risk of cardiovascular disease.2–5 the relationship in the development of atherosclerosis is illustrated by the
between decreasing renal function and increasing rates observation that osteopetrotic mice, which lack macro
of cardiovascular disease and mortality is due to multiple phage colonystimulating factor, have low numbers
mechanisms, including abnormal myocardial remodel of macrophages in their atherosclerotic lesions and a
ing, ventricular hypertrophy, arrhythmia and cardiac small lesion area, even in the presence of severe hyper
arrest; the influence of these factors depends on the lipidemia.9 macrophages also have a central role in innate
level of CKD. Compared with the prevalence of athero immunity.10 the interaction between antigenpresenting
sclerotic disease in individuals with intact kidney func dendritic cells and t cells activates the adaptive immune
tion, however, atherosclerotic disease is overrepresented response and defines the inflammatory processes of early
across the entire spectrum of patients with CKD. atherogenesis. ligation of CD40 on activated t cells leads
macrophages have critical roles in all stages of athero to enhanced production of t helper (tH) 1 cell cytokines,
sclerotic lesion formation and mounting experimental including interferon γ,11 which is proatherogenic.12 this
evidence implicates their importance in the vascular tH1 cytokine cascade is counterbalanced by the presence
complications of renal disease. of antiatherogenic tH2 cytokines, including interleukin Department of
macrophages contribute to all stages of atherosclerosis (il)10.13 this review focuses on the mechanisms of Pediatrics (V. Kon),
through their role in inflammation and lipid homeostasis.6 CKDinduced atherosclerosis, with particular empha Department of
Medicine (M. F. linton,
retention of atherogenic lipoproteins in the arterial sis on the role of macrophages, as demonstrated by S. Fazio), Vanderbilt
intima prompts the production of leukocyte chemo experimental studies and data from clinical studies. University Medical
Center, 383 Preston
attractant molecules. these molecules activate receptors Research Building,
on rolling monocytes, which leads to their initial adhe Macrophages and atherosclerosis 2220 Pierce Avenue,
sion mediated by selectins, followed by their integrin the accumulation of macrophages laden with chole Nashville, TN
37332‑6300, USA.
dependent adhesion to the endothelium and their sterol ester in the arterial intima is the hallmark of fatty
streak formation in humans and experimental models. Correspondence to:
S. Fazio
Competing interests macrophages internalize atherogenic lipoproteins (such sergio.fazio@
The authors declare no competing interests. as oxidized lDl) via scavenger receptors, including vanderbilt.edu
vCam1 are strong independent predictors of poor oxidative stress in patients with mild to moderate CKD
outcome in patients with CKD.43 uremic serum increases and patients with esrD on hemodialysis,64–66 no large
the expression and shedding of adhesion molecules by clinical trials have been conducted to evaluate the effi
vascular endothelial cells.44 the coronary plaques of cacy of such interventions on the risk of cardiovascular
patients with CKD (particularly calcified plaques) have events or death in these populations. indeed, largescale,
increased expression of the inflammatory markers longterm followup studies of vitamin e supplementa
CD40–CD154 and of Creactive protein. 45 notably, tion in individuals with normal renal function have been
peripheral leukocytes of patients with CKD have greater disappointing.67,68 nonetheless, CKD increases oxidative
responses to inflammatory and oxidative stimuli than stress, thus creating an optimal set up for antioxidant
those of healthy controls.46–48 even without stimulation, therapies to target macrophage infiltration and function.
circulating granulocytes and monocytes of patients on However, currently available antioxidant therapies might
dialysis produce elevated levels of superoxide and hydro not be sufficiently effective to influence the complexi
gen peroxide, and have greater expression of CD11b/ ties that underlie the increased mortality rates in patients
CD18 integrins than those of healthy individuals. 47 with CKD.
in addition, monocytes from patients with endstage
renal disease (esrD) have suppressed levels of anti Macrophage egress
inflammatory cytokines and seem to be more susceptible in addition to increased cellular infiltration, the vascular
to macrophage transformation than cells from normal accumulation of macrophages in CKD might be caused
controls. 46 such observations support the idea that by their increased survival or decreased egress from
CKD increases systemic inflammation, vascular micro the vascular wall (Figure 1). transplantation of athero
inflammation and macrophage priming, all of which can sclerotic aorta from hyperlipidemic Apoe–/– mice into
amplify the expression of cytokines by macrophages and normolipemic wildtype mice results in plaque regres
their recruitment into the subendothelial space. sion and the loss of foam cells into the local lymphatic
a major contributor to heightened inflammation is the system and circulation.23,69,70 substantial foamcell exit
enhanced oxidative stress that develops early in CKD, is observed within 3 days of transplantation. the resolu
persists as renal function declines, and is not improved tion of the atheroma under these conditions also includes
by dialysis treatment. 47–52 urea, at disease relevant abatement in areas of necrosis, extracellular accumulation
concentrations, stimulates the generation of reactive of cholesterol, and fibrosis.71 in a 2010 study, renal abla
oxygen species in vitro and in vivo.53 Factors that promote tion has been shown to inhibit macrophage emigration
oxidative stress in the setting of CKD include naDPH out of the vessel wall.72 transplantation of atheromatous
oxidase, uncoupled endothelial nitric oxide synthase and aortic segments from Apoe–/– mice into normolipemic
myeloperoxidase.49,54,55 myeloperoxidase is a predictor of mice after renal ablation did not cause plaque regres
cardiovascular disease risk and is abundantly expressed sion as seen after transplantation of atheromatous aortic
by neutrophils and macrophages within athero segments from Apoe–/– mice into normolipemic recipient
sclerotic lesions in patients with CKD.56,57 Compared mice with intact kidneys. on the contrary, the plaques of
with healthy controls, leukocyte lysate from patients with renalablated normolipemic recipients actually expanded
CKD has increased myeloperoxidase activity, which is and contained more macrophages than those of recipi
not improved by dialysis.46 a single nucleotide poly ents with intact kidneys. the increased macrophage
morphism in the promoter region of the myeloperoxidase content was not linked to changes in cellular survival and
gene has been associated with reduced expression of macrophages within the plaques of renalablated mice
myeloperoxidase and linked to reduced prevalence showed downregulation of serum response factor target
of cardiovascular disease in patients with CKD and genes and upregulation of the migration factor CCr7. in
esrD. 58,59 treatments that decrease oxidative stress view of the dynamic nature of the atherosclerotic plaque,
and inflammation, such as Nacetylcysteine or neutraliz impaired plaque regression and decreased macrophage
ing antibodies against the receptor for advanced glycation emigration in the setting of renal damage might contrib
end products, significantly reduce experimental athero ute not only to accelerated atherosclerosis, but also to
sclerosis caused by renal dysfunction.60,61 moreover, and the lack of vascular benefits from treatments that lower
in contrast with results in the general population, anti plasma lipids in advanced CKD.
oxidative therapy substantially reduces cardiovascular
morbidity in patients with CKD. 62,63 For example, Macrophage trapping
Nacetylcysteine has been shown to decrease concen CKDinduced changes within the local vascular milieu
trations of oxidized lDl cholesterol by 76% and the and modulation of macrophage function may cause sub
composite end points of nonfatal myocardial infarction, endothelial trapping of macrophages (Figure 1). CKD
cardiovascular death, revascularization and ischemic increases the oxidation and glycosylation of matrix mol
stroke by 40% in patients with stage 5 CKD.62,63 in these ecules including proteoglycans, collagen, and elastin.73,74
same small studies, antioxidant therapy with vitamin e modifications of extracellular matrix promote lipoprotein
reduced the rate of cardiovascular end points by >50% retention and oxidation and lead to increased cholesterol
and the rate of myocardial infarction by 70% in patients accumulation by the macrophage, resulting in increased
on hemodialysis.62,63 although antioxidant therapies cholesterol content in the cellular membrane, which
decrease levels of electronegative lDl and biomarkers of causes stiffness and impaired cellular mobility.75,76
with human aPoai did not reduce the atherosclerotic activity, which is not altered by dialysis. 85,112,115–118
burden of nephrectomized Apoe–/– mice.99 However, this Furthermore, HDl from patients on hemodialysis does
intervention did lessen the lipid and collagen content not protect lDl from oxidation,118 whereas the addi
of the atherosclerotic plaques and increased the area tion of an aPoai mimetic peptide to lDl obtained
occupied by smooth muscle cells—changes that could from patients on dialysis reduces its capacity to increase
be indicative of plaque stabilization.99 monocyte chemotactic activity in cultured endothelial
in addition to modulating cholesterol homeostasis, cells.118 taken together, these observations suggest that
aBCa1 has major antiinflammatory and antiapoptotic severe CKD influences the composition and function of
functions.90 macrophages from abca1deficient mice lDl and HDl, as well as macrophage gene expression, to
have increased tolllike receptor (tlr) signaling, which cause perturbations that are not necessarily targeted by
enhances their inflammatory response to lipopoly current lipidlowering interventions. whether extreme
saccharide and other tlr ligands.100,101 upregulation reductions in lDl level have cardiovascular benefits in
of tlr2 and tlr4 has been reported in monocytes of patients with esrD remains unknown, but the answer
dialysis patients with systemic inflammation,102 whereas to this question might come from studying the direct
expression of these receptors was reportedly decreased in cellular effects of statin therapy. statins suppress chole
dialysis patients with low levels of Creactive protein.103 sterol synthesis and reduce intracellular concentrations
aBCa1 also directly suppresses lipopolysaccharide of oxysterols and isoprenoids, intermediaries that influ
induced inflammatory cytokine production by macro ence nuclear receptors and G proteins to modulate sig
phages through a pathway that involves signal transducer naling pathways and gene expression. the effect of statins
and activator of transcription 3 and is independent of on these pathways is influenced by cholesterol content
cholesterol export.96 in view of the chronic systemic and and by cellular activation and differentiation.119–125 For
vascular inflammation that prevails in CKD, repressed example, the downregulation of aBCa1 level induced by
aBCa1 function in macrophages might be especially statins is more pronounced with increased macrophage
detrimental through suppression of lipid export and differentiation and less pronounced with increased
activation of the inflammatory response. cholesterol loading of the cell.119 it is therefore possible
that the activated macrophages of patients with advanced
CKD and lipoproteins CKD do not respond normally to statin stimulation
CKD influences lipoproteins that are involved in macro owing to their abnormal content and distribution of
phage function. CKD generates both atherogenic lDl and cellular lipids.
dysfunctional HDl particles. Plasma levels of modified
and oxidized lDl, which correlate with cardiovascular CKD activation of angiotensin II
event rates in the general population,104 are elevated at CKD activates the renin–angiotensin system (ras),
all stages of CKD.105 myeloperoxidasegenerated reactive which leads to heightening of its principal effec
nitrogen species facilitate lipid peroxidation and protein tor peptide, angiotensin ii, and ultimately modula
nitration, which enables lDl to be avidly taken up by tion of macrophage function. antagonism of the ras
CD36.55,106 Furthermore, the catalysis of lDl carbamyla by angiotensinconvertingenzyme (aCe) inhibitors
tion by myeloperoxidase reduces the affinity of lDl for or angiotensiniireceptor blockers (arBs) is the corner
the lDl receptor and increases its affinity for scavenger stone of treatment of progressive renal failure. 126,127
receptors.55,107 such findings suggest that CKD might be angiotensin ii is also a major driving force in athero
associated with modifications in the composition and sclerosis. numerous epidemiological studies document
function of lDl that promotes atherosclerosis, but is not fewer cardiovascular events and increased survival in
affected by lipidlowering therapy.108,109 individuals treated with antagonists or inhibitors of
CKD also affects HDl levels and function. low levels angiotensin ii.128,129 notably, these benefits are indepen
of HDl cholesterol are a powerful negative risk factor dent of hemodynamic effects and underscore a more
for cardiovascular disease, prevail at all stages of CKD direct role for angiotensin ii in cardiovascular and
and, as in the general population, are associated with renal diseases. the levels, duration, and localization of
increased mortality.110 experimental and clinical studies angiotensin ii activation that are necessary to activate
demonstrate that several factors contribute to the low these disease pathways are unknown. activated angio
level of HDl in CKD, including reduced levels of aPoai, tensin ii in CKD can potentiate macrophage infiltration
enriched levels of serum amyloid a, and decreased of the arterial intima in every stage of atherogenesis.
lecithin–cholesterol acyltransferase function. 84,85,110–112 experimentally, a sustained increase in circulating
CKD also impairs HDl maturation, which can pro levels of angiotensin ii through exogenous infusion
foundly compromise many of its protective functions. causes recruitment of macrophages along with vascular
For example, under normal conditions HDl fractions inflammation, lesional neovascularization, hemorrhage
contain antioxidant enzymes such as paraxonase and and elastolysis in hyperlipidemic mice and rabbits.130–135
glutathione peroxidase.113,114 However, the accumulation in clinical settings, shortterm elevations in angio
of advanced glycation end products and acrolein in CKD tensin ii activity, such as hypotension, volume depletion,
reduces the levels of these enzymes, compromising HDl and cardiac ischemia, might have delayed consequences
function. indeed, HDl from patients with esrD has on atherosclerosis. we examined whether transient
markedly reduced antioxidant and antiinflammatory elevations in levels of angiotensin ii can affect future
plaque development, and found that athero sclerosis inhibition of the action of angiotensin ii with aCe
was dramati cally increased in Apoeknockout mice inhibitors or arBs reduces the risk of cardiovascular
3 months after a 2week infusion of a nonhypertensive events in individuals with normal renal function.
dose of angiotensin ii.130 as the amplification of athero experimental findings suggest similar benefits in patients
sclerosis did not occur during angiotensin ii infusion, with CKD. we showed that atherosclerosis after uni
these results confirm that angiotensin ii activates mecha nephrectomy in Apoe–/– mice is dramatically lessened by
nisms that promote and amplify atherogenic processes. antagonism of angiotensin ii with losartan but not with
indeed, angiotensin ii exposure caused an immediate the nonspecific antihypertensive agent, hydralazine.35 the
increase in the vascular messenger rna expression of reduction in the atherosclerotic burden with losartan
several chemoattractants (including CCl2 and its recep treatment was accompanied by changes in plaque com
tor CCr2) and a subsequent accumulation of macro position that included fewer macrophages. moreover,
phages in the aorta of angiotensiniiinfused mice.130 in vitro macrophage migration was reduced by arB
interestingly, our ex vivo study found that macrophages treatment. these effects on macrophage infiltration were
harvested from angiotensiniiinfused mice had sub accompanied by the preservation of extracellular matrix
stantially increased migration across the cell mem components, especially elastin, and decreased levels of the
brane in response to CCl2 chemotaxis.136 moreover, proteolytic enzyme, cathepsin s. none of these benefits
angiotensin ii amplifies atherosclerosis and increases were observed in hydralazinetreated mice.
macrophage content in the aorta of mice carrying Apoe–/– as discussed above, a reduction in renal mass by
macrophages.136 Conversely, inhibition of angiotensin ii uninephrectomy decreases cholesterol efflux in macro
reduces macrophage infiltration and promotes compo phages via repression of the macrophage aBCa1
sitional changes such as increased collagen content that transporter.91 In vivo treatment with an arB restored
might stabilize the atherosclerotic plaque.137,138 macrophage abca1 expression in the macrophages of
the modulation of macrophagespecific functions by uninephrectomized Apoe–/– mice. these results comple
angiotensin ii is supported by observations that mono ment previous in vivo and in vitro findings demon
cytes and macrophages express all components of the strating that exogenous angiotensin ii downregulates
ras, including type1 (at1) and type2 (at2) angio aBCa1.150,151 Furthermore, incubation of human and
tensin ii receptors.139–141 In vitro, angiotensin ii increases mouse macrophages with arBs, especially, telmisartan,
the macrophagemediated modification and uptake of increased cholesterol efflux via a peroxisome proliferator
lDl, cholesterol synthesis in macrophages, differentiation activated receptor γdependent pathway, which caused
of monocytes to macrophages, activation of macrophage an upregulation of aBCa1 level.150–153 taken together,
generated oxidative stress, and levels of proinflammatory these observations suggest a pivotal importance of
cytokines.142 monocytes from patients with hypertension angiotensin ii–aBCa1 interaction for cholesterol
have high numbers of at1 receptor in dimer form, which homeostasis in macrophages in the setting of renal dys
correlates with increased angiotensiniidependent function, which provides a basis for possible modulation
adhesion to endothelial cells.143,144 of excess risk of cardiovascular disease in patients with
the functional importance of the macrophage at1 CKD. interestingly, in vivo treatment of Apoe–/– mice
receptor in modulating atherosclerosis in vivo is illustrated with the arB losartan substantially attenuated upregula
by studies using chimeric mice in which the at1 recep tion of nFκB subfamily proteins rela and p50, suggest
tor (atgr1) is either ablated or expressed exclusively in ing a potential key regulatory step in this pathway in
hematopoietic cells.145–148 transplantation of bone marrow cholesterol efflux.91 arB treatment was also found to
from Atgr1knockout mice into atherosclerosisprone have suppressive effects on nFκB in other tissues.95,154
mice lacking either apoe or the lDl receptor did not CKDinduced activation of angiotensin ii can
markedly alter their atherosclerotic lesions.145,147 infusion also derange lipoprotein composition and function.
of angiotensin ii increased atherosclerosis and macro angiotensin ii promotes lDl oxidation and impairs
phage infiltration in Apoe–/– mice that had received bone maturation of HDl, whereas inhibition of angiotensin ii
marrow from Atgr1+/+ mice but not in Apoe–/– mice that action has opposite effects. 138,142,153–156 indeed, aCe
had received bone marrow from Atgr1knockout mice. inhibitors substantially reduced lipid myeloperoxidase
likewise, reconstitution of Ldlrknockout mice with bone mediated oxidation of lDl,157 oxidizedlDlmediated
marrow from Atgr1+/+ mice or Atgr1knockout mice pro transformation of cultured macrophages into foam
duced the same results.145,147 By contrast, Atgr1knockout cells,158 and levels of oxidized lipoproteins in the serum
mice reconstituted with bone marrow from Atgr+/+ mice and arteries of hypercholesterolemic rabbits and mice.159
had increased atherosclerosis and decreased collagen although experimental findings suggest that antagonism
content after exposure to angiotensin ii, consistent with of angiotensin ii might benefit patients with CKD, clini
the phenotype of a more unstable lesion. these findings cal studies remain sparse. Post hoc analysis of aCe
suggest that in an angiotensiniiheightened state, such inhibitor treatment in patients with mild to moderate
as CKD, the macrophage at1 receptor is responsible for renal impairment found an increased reduction in risk of
acceleration and destabilization of plaques.35 in this way, cardiovascular events in these individuals than in those
increased expression of aCe by circulating monocytes without compromised renal function.2,160 However, an
correlates with cardiovascular events and mortality in inclusive evaluation of studies of aCe inhibitor or arB
patients on hemodialysis.149 treatment on cardiovascular outcomes in patients with
CKD, including esrD, did not allow a clear and defini of the ras and are responsive to treatment with
tive interpretation of the findings. some studies did not agents that reduce vascular exposure to angiotensin ii.
find a benefit of angiotensin ii inhibition,161–163 while interventions that modulate macrophage behavior via
many others, including a large metaanalysis,164 report antagonism of angiotensin might produce vascular
that patients with advanced CKD treated with aCe benefits across the spectrum of CKD.
inhibitors or arBs have fewer cardiovascular events and
reduced mortality.165–171 Review criteria
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25, 2265–2272 (2010). patients receiving peritoneal dialysis. A all aspects of this manuscript.