Although it is established that monocyte/macrophage-derived foam cells have a central role in the development of atherosclerosis, the pathophysiological significance of these cells in the kidney has been a puzzle for many years. Renal pathologists commonly encounter these cells in human renal biopsies in diverse disease settings. These include diabetic nephropathy, and the tip and cellular variant forms of focal and segmental glomerulosclerosis (FSGS), in which glomerular capillaries may appear occluded by an infiltrate of these cells (Fig. 1) [1,2]. Dissolution of the normally compact mesangial matrix (‘mesangiolysis’) frequently is present in conjunction with glomerular foam cell accumulation, but whether these processes are mechanistically linked remains unknown. Rare glomerular diseases in humans characterized by foam cell accumulation include immune-mediated acquired lecithin–cholesterol acyltransferase deficiency  and a glomerulopathy associated with a homozygous mutation of apolipoprotein E (ApoE) – ApoE2 . Foam cells commonly populate the interstitium in nephrotic states and in Alport syndrome, and at least one study has suggested that these cells contribute to progressive tubulointerstitial injury and are associated with a higher prevalence of concurrent FSGS regardless of primary disease cause . However, the evidence linking renal interstitial foam cells to chronic kidney disease (CKD) in human or experimental disease is scanty. Indeed, it is our impression that many observers regard these cells as bystanders in renal disease states that are unlikely to have clinical significance. Although the central questions of whether or how these cells are pathogenic in the kidney cannot be answered definitively at present, new insights concerning monocyte and macrophage biology may provide guidance in our thinking about how these cells may participate in kidney disease.
Although lipid-laden foam cells may be derived from a variety of cell types, including smooth muscle cells, mesangial cells, epithelial cells, endothelial cells, and resident phagocytic cells such as Kupffer cells in the liver, it is the lipid-laden monocyte/macrophage-derived foam cell that remains the best studied, with well-established pathogenic properties [6,7▪▪,8▪,9▪▪,10]. These cells are central to the development and progression of atherosclerotic plaques [11▪▪], and it is these cells that are the subject of this review. This class of foam cells arises in response to metabolic conditions that promote intracellular uptake of lipoproteins and cholesterol or concurrent dysfunction of homeostatic mechanisms that normally allow egress of cholesterol and lipids from cells.
FOAM CELLS ARE PATHOGENIC IN ATHEROSCLEROSIS
Generation of foam cells derived from monocytes/macrophages is the result of three broad processes: excessive influx of cholesterol and lipid into the cell; metabolic modification of cholesterol, primarily by esterification; and impaired egress of cholesterol back into the circulation (a process known as reverse cholesterol transport). The details of these processes have been well reviewed [7▪▪,12]. In the setting of atherosclerosis, the first steps in foam cell formation are the uptake of local accumulations in artery walls of oxidized and acetylated low-density lipoproteins by monocytes/macrophages. Binding to matrix proteins such as proteoglycans is a major factor that causes these lipoproteins to lodge in the arterial intima wherein atherosclerosis is initiated. Uptake by monocytes/macrophages primarily occurs through several scavenger receptors, principally CD36 and scavenger receptor A, although other processes including macropinocytosis and phagocytosis contribute . There are no data currently available that address the issue of whether the local accumulation of foam cells in the kidney is similarly initiated. The nature of scavenger receptor interactions with lipoproteins is not straightforward. For instance, the disorder lipoprotein glomerulopathy is characterized by abnormal accumulations of ApoE containing ‘lipoprotein thrombi’ within glomerular capillaries, but typically without prominent foam cell formation . Lipid accumulation per se (so-called ‘fatty kidney’) is not sufficient for renal macrophage foam cell accumulation [9▪▪]. Foam cell formation in arteries is regulated in part by cytokines and mediators of inflammation including interleukin-33, interferon-γ, and transforming growth factor-β, contributing to the concept that this process and atherosclerosis can be considered, at least in part, as an inflammatory injury [12,13]. As reviewed by Moore et al. and Randolph [16▪▪], there is evidence that macrophages and foam cells in atherosclerosis may be the result of engagement of both innate and adaptive immune pathways, and, in turn, these cells likely contribute to the amplification of these pathways by such functions as antigen processing and presentation and providing damage-associated molecular pattern signals.
Foam cell accumulation in the intima of large arteries marks the initiation of atherosclerosis in both human disease and well established animal models such as fat-fed nonhuman primates and rabbits, and in genetically mutated mice with hyperlipidemia such as ApoE−/− and low-density lipoprotein receptor (LDLR−/−)-deficient mice . Necrobiosis of foam cells leads to instability and rupture of atherosclerotic plaques. Maneuvers that reduce or eliminate macrophage accumulation in experimental atherosclerosis also reduce or prevent the formation of atherosclerotic plaques, as exemplified by ApoE−/− and LDLR−/− mice in which the two main components of the principle chemokine homing system for macrophages (monocyte chemoattractant protein-1 and its receptor CCR2) have also been genetically deleted [18,19]. Finally, the phenotypic characterization of foam cells in atherosclerotic plaques has revealed several mechanisms of their pathogenicity, including production and secretion of reactive oxygen species (ROS), production and secretion of oxidized lipoproteins, activation and secretion of metalloproteinases, and secretion of proinflammatory cytokines and growth factors that promote sclerosis [10,11▪▪,16▪▪,20–24].
NEED FOR ANIMAL MODELS OF FOAM CELLS IN THE KIDNEY
The genesis of this review began as a reconsideration of a once-influential hypothesis article by Diamond and Karnovsky  that proposed that FSGS was analogous to atherosclerosis. Their conclusion was based on identified similarities of mesangial cells in cases of FSGS to the vascular smooth muscle-like cells that are one of the principal cell types found in atherosclerotic plaques, and the ubiquitous presence of monocyte-derived foam cells, the other major cell type found in atherosclerotic plaques . More recently, a substantial body of epidemiologic evidence clearly demonstrates strong links between CKD and atherosclerotic cardiovascular disease (ASCVD), and it has been shown that the increased cardiovascular mortality in patients with diabetes is attributable to the nephropathy that occurs in the subset of patients with this complication [26–28]. Indeed, the tight link between ASCVD and CKD extends beyond diabetes, as it now well established that ASCVD is the main cause of death in patients with CKD . The need to identify and understand common pathogenic mechanisms that may underlie atherosclerosis and CKD remains unmet. We must ask: Is it correct that what is true in atherosclerosis can be reliably extrapolated to the kidney? Are foam cells important contributors to chronic and sclerosing renal injury? Are foam cells in aortas and large arteries biologically identical to those found in the kidney, and are those found in the glomerulus identical to those found in the renal interstitium?
The answers to these critical questions are unknown and rarely addressed in the renal literature. This likely is the result of a lack of good model systems in which these concepts can be tested. Unlike the case with atherosclerosis, there are no robust animal models of foam cell accumulation in the kidney. We have published our experience with three models of hyperlipidemic renal injury: the ApoE−/− mouse , the LDLR−/− mice , and the fat-fed B6.ROP Os/+ mouse with reduced nephron number . We have shown that these mice, when maintained for extended periods of time on a ‘Western’ high-fat diet (>32 weeks), spontaneously develop progressive glomerular foam cell accumulation, mesangiolysis, and tubular injury (Fig. 2), but neither we nor others have studied these models for lengthier periods of time to determine whether this additional step will lead to the development of CKD. Although we have established temporal sequences of foam cell accumulation and mesangiolysis and sclerosis in our mouse models, neither we nor others have tested whether these associations are indeed causal.
There are important deficiencies of these models that need to be overcome in order to facilitate the testing of concepts of renal pathogenicity of foam cells. The development of foam cell lesions has not been sufficiently widespread in glomeruli in the models cited earlier to allow robust experimental studies of foam cell pathogenicity to the kidneys. The structural changes that are present have not led to progressive CKD, and so, without further modification, these mice cannot serve as good model systems for the combined CKD and ASCVD that are so lethal to patients with kidney disease. In efforts to overcome this deficiency, animal models of ASCVD such as ApoE−/− and LDLR−/− mice have been subjected to further modifications such as partial nephrectomy  or administration of a renal toxin such as adriamycin, or introduction of specific gene mutations in order to induce CKD in the setting of ASCVD that is already present, in order to model the situation in humans with CKD [34▪,35]. Recent examples of such modifications include the study of Tavori et al. that overexpressed variants of ApoE specifically in macrophages in both ApoE−/− and combined ApoE−/−/LDLR−/− mice. This study found that macrophage-specific expression of a variant of ApoE (ApoESendai) linked to the development of lipoprotein glomerulopathy in humans is protective against atherosclerosis but causes lesions of lipoprotein glomerulopathy to develop in combined ApoE−/−/LDLR−/− mice. Interestingly, the glomerular lesions were reported to include foci of mesangiolysis, but the presence of foam cells was not described. The study of Kennedy et al.[34▪] focused on ApoE−/− mice with the additional deletion of the CD36 scavenger receptor. Fat-fed ApoE−/−/CD36−/− mice had less macrophage accumulation, glomerular foam cell accumulation, and interstitial fibrosis, and improved creatinine clearance compared with fat-fed ApoE−/− controls. However, as noted above, CKD has not been shown to reliably develop in the ApoE−/− mouse model, and the degree of interstitial fibrosis was not substantial in any of the study groups. The concurrence of diminished foam cell prevalence with improvement in measured renal function offers support for the proposition that these cells are indeed pathogenic in the kidney, and so this model offers potential for further studies to validate this injury process.
Studies by Wang et al. have shown that altered lipid metabolism, in general, and increased expression of sterol regulatory element-binding proteins 1 and 2 (SREBP-1 and 2) contribute to diabetic kidney disease. SREBP-1 and 2 are transcription factors that promote lipid and cholesterol accumulation in the kidney; mice that overexpress SREBP-1 develop a sclerosing glomerulopathy and proteinuria. Studies involving these proteins, particularly the nuclear hormone receptor farnesoid X receptor (FXR), which regulates SREBP expression, indicate that manipulating this pathway by overexpressing FXR activity can have a beneficial effect in an experimental model of diabetic nephropathy . Particularly noteworthy is the accumulation of foam cells, accompanied by mesangiolysis, in FXR-deficient mice made diabetic by streptozotocin administration . We are unaware of other mouse models of diabetic nephropathy that have such a prominent accumulation of foam cells. Curiously, this finding occurred in a mouse model (streptozotocin-treated C57BL/6 mice) known to be resistant to developing structural changes of diabetic nephropathy . This is one of the few mouse models in which foam cell formation and mesangiolysis can be induced, and is deserving of further studies that might identify mechanisms that link these two processes. The availability of specific antagonists to FXR may be especially useful in pursuing such studies.
GLOMERULAR FOAM CELLS AND FOCAL AND SEGMENTAL GLOMERULOSCLEROSIS
In FSGS, glomerular capillaries are segmentally occluded by relatively acellular material including matrix proteins and hyalin. The tip lesion and cellular variants of FSGS in particular may manifest expansile lesions stuffed with foam cells [1,2]. These variants of FSGS often demonstrate a confluence of swollen and hypertrophied podocytes in conjunction with the intracapillary foam cell accumulation. To date, there has been little evidence to link glomerular foam cell accumulation to podocyte injury per se, but a recent abstract presented at the 2014 Annual Meeting of the American Society of Nephrology by the group of Nagata used a dual mouse model of hyperlipidemia (LDLR−/− mice) crossed with the NEP25 model of podocyte depletion induced by administration of the immunotoxin LMB. An exciting finding was the preferential accumulation of foam cells to those glomerular capillaries exhibiting significant podocyte loss . The authors postulated a sequence of injury whereby initial podocyte injury leads to disordered lipid metabolism and endothelial and mesangial injury, in turn leading to induction of cytokines that then leads to recruitment of macrophages and foam cell formation at the site of injury . This would imply that foam cells are relative latecomers to the injury process, but establishing the chronology of podocyte injury and foam cell accumulation in FSGS will require further testing. Indeed, it might be possible to use such a model to test an alternate scenario whereby foam cell formation occurs early in the injury process, and then test whether local uptake of oxidized low-density lipoproteins or acetylated low-density lipoproteins by macrophages initiates the process of foam cell formation as it does in atherosclerosis. These studies are particularly exciting in that they offer a plausible model for studies of lesions such as tip and cellular variants of human FSGS in which both foam cell accumulation and podocyte injury are important features.
FOAM CELLS: TRANSIENT VISITORS OR INDIGENOUS POPULATION?
It has been commonly thought that mature tissue macrophages originate from bone marrow-derived hematopoietic cells, traveling through the circulation as monocytes and settling in tissues as part of either injury or reparative processes. Such cells may reside in the kidney for short periods of time, leaving by a return to the circulation or by cell death, or they may extend their stay but with little capacity for self-renewal. Very recent studies, reviewed by Sieweke and Allen , challenge this paradigm. In aggregate, these studies indicate that populations of tissue-based macrophages may originate from embryonic precursors that are tissue specific and hence may not be of bone marrow origin. Furthermore, mature tissue-based macrophages have a capacity to self-renew by local proliferation [40▪]. This suggests that macrophage-derived foam cells in the kidney may not necessarily come from the circulation, and hence strategies to block monocyte/macrophage recruitment to sites of injury, such as blocking local production of chemokines or blockade of chemokine receptors, may have little or no effect on the accumulation of such cells in disease states. It also raises the possibility that a fixed or locally self-renewing population of cells may acquire or abandon a foam cell phenotype in response to local stimuli.
FOAM CELLS AS THERAPEUTIC TARGETS
The pathogenicity of foam cells in atherosclerosis has led to the exploration of multiple therapeutic strategies to modulate their pathogenic activities. Such strategies could prove useful should such cells be shown to have effects in the kidney that promote disease. One major approach includes the enhancement of egress of cholesterol from these cells. Cholesterol egress can occur by several routes, mediated by membrane transport proteins, including adenosine triphosphate-binding cassette transporter A1, adenosine triphosphate transporter G1, and scavenger receptor class B member-1 [6,12,15]. The liver X receptor is a transcription factor that promotes reverse cholesterol transport out of the cell through these pathways [15,24]. When these pathways are disrupted (e.g., deletion of adenosine triphosphate-binding cassette transporter A1 and adenosine triphosphate transporter G1 in macrophages), these cells show increased lipid accumulation and increased atherosclerotic lesion severity . Several therapeutic agents have been shown to be atheroprotective in model systems acting directly or indirectly on these pathways. These include taurine, the 5’ adenosine monophosphate activated protein kinase (AMPK) activator AICAR, activators of heme-oxygenase-1, and peroxisome proliferator-activated receptors α and γ agonists such as glitazones [12,15,24].
Mitochondrial oxidative stress has been increasingly identified as a key early pathogenic event in glomerular diseases (diabetic nephropathy and FSGS) that can have foam cell accumulation [42–44]. Although ROS have been identified in lesional monocytes/macrophage of atherosclerosis  for some time, exciting recent studies by Wang et al.[46▪▪] have shown that enhanced expression of catalase, a scavenger of ROS, when restricted to mitochondria of monocytes/macrophages, reduces oxidative stress and results in marked reduction of foam cell accumulation and other features of atherosclerosis in LDLR−/− mice. Reduction of ROS is an attractive therapeutic strategy for the amelioration of potential deleterious effects of foam cells in the kidney, as such strategies are already being tested for their potential benefit in some forms of kidney disease, such as acute kidney injury and diabetic nephropathy. Following the example in the LDLR−/− mouse, interventions to reduce mitochondrial oxidative stress could be used to both establish the pathogenicity of renal foam cells and potentially provide therapeutic benefit if a robust model of foam cell accumulation in kidney disease could be developed for testing such strategies.
The goal of this review was to assess whether renal foam cells are pathogenic in the kidney, or not. Sadly, the information currently available does not allow a meaningful answer to this question. A critical issue has been the limited availability of animal models that robustly produce foam cell accumulations in kidney disease settings analogous to human diseases. The animal models of FSGS commonly employed (renal ablation, administration of glomerular toxins such as adriamycin or puromycin aminonucleoside, and genetic deletions of podocyte or basement membrane proteins) do not possess this feature. Indeed, good animal models of the tip variant of FSGS await development, although the mouse model of podocyte ablation in a hyperlipidemic setting may prove to be such a model. Although a useful animal model of Alport syndrome, the COL4 (collagen IV alpha 3 chain) null mouse, has been developed, descriptions of this model to date have not identified a component of interstitial foam cell accumulation. There are opportunities for model development that may enable an answer to the question of pathogenicity. If models of foam cell accumulation in glomeruli such as the ApoE−/− mouse and the LDLR−/− mouse could be made more robust, the pathogenicity of the foam cells could then be studied by such currently available techniques as macrophage ablation or modulation of specific monocyte/macrophage function strategies akin to those employed in studies of atherosclerosis.
Financial support and sponsorship
This work was supported by a grant from the National Institute of Health (DK83391) and supported in the past by a grant from the Genzyme GRIP program.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
1. Stokes MB, Valeri AM, Markowitz GS, D’Agati VD. Cellular focal segmental glomerulosclerosis: clinical and pathologic features. Kidney
Int 2006; 70:1783–1792.
2. D’Agati VD, Kaskel FJ, Falk RJ. Focal segmental glomerulosclerosis. N Engl J Med 2011; 365:2398–2411.
3. Takahashi S, Hiromura K, Tsukida M, et al. Nephrotic syndrome caused by immune-mediated acquired LCAT deficiency. J Am Soc Nephrol 2014; 24:1305–1312.
4. Kawanishi K, Sawada A, Ochi A, et al. Glomerulopathy with homozygous apolipoprotein e2: a report of three cases and review of the literature. Case Rep Nephrol Urol 2013; 3:128–135.
5. Wu Y, Chen Y, Chen D, et al. Presence of foam cells in kidney
interstitium is associated with progression of renal injury in patients with glomerular diseases. Nephron Clin Pract 2009; 113:c155–c161.
6. Yu XH, Fu YC, Zhang DW, et al. Foam cells in atherosclerosis
. Clin Chim Acta 2013; 424:245–252.
7▪▪. Hopkins PN. Molecular biology of atherosclerosis
. Physiol Rev 2013; 93:1317–1542.
An almost unimaginably comprehensive review on the pathophysiology of atherosclerosis, including a current review of the mechanism of foam cell formation.
8▪. Chaabane C, Coen M, Bochaton-Piallat ML. Smooth muscle cell phenotypic switch: implications for foam cell
formation. Curr Opin Lipidol 2014; 25:374–379.
A reminder that not all foam cells are of macrophage origin!
9▪▪. de Vries AP, Ruggenenti P, Ruan XZ, et al. Fatty kidney
: emerging role of ectopic lipid in obesity-related renal disease. Lancet Diabetes Endocrinol 2014; 2:417–426.
An important review of the pathology by which lipid may have deleterious effect on the kidney and with an overall focus on obesity-related renal injury.
10. Shashkin P, Dragulev B, Ley K. Macrophage
differentiation to foam cells. Curr Pharm Des 2005; 11:3061–3072.
11▪▪. Zeller I, Srivastava S. Macrophage
functions in atherosclerosis
. Circ Res 2014; 115:e83–e85.
A succinct review of the pathogenicity of macrophages in atherosclerosis, with a focus on the development of foam cells.
12. McLaren JE, Michael DR, Ashlin TG, Ramji DP. Cytokines, macrophage
lipid metabolism and foam cells: implications for cardiovascular disease therapy. Prog Lipid Res 2011; 50:331–347.
13. Michael DR, Ashlin TG, Davies CS, et al. Differential regulation of macropinocytosis in macrophages by cytokines: implications for foam cell
formation and atherosclerosis
. Cytokine 2013; 64:357–361.
14. Saito T, Matsunaga A. Lipoprotein glomerulopathy may provide a key to unlock the puzzles of renal lipidosis. Kidney
Int 2014; 85:243–245.
15. Moore KJ, Sheedy FJ, Fisher EA. Macrophages in atherosclerosis
: a dynamic balance. Nat Rev Immunol 2013; 13:709–721.
16▪▪. Randolph GJ. Mechanisms that regulate macrophage
burden in atherosclerosis
. Circ Res 2014; 114:1757–1771.
A comprehensive review of macrophage biology in the setting of atherosclerosis.
17. Ross R. Atherosclerosis
: an inflammatory disease. N Engl J Med 1999; 340:115–126.
18. Rollins BJ. Chemokines and atherosclerosis
: what Adam Smith has to say about vascular disease. J Clin Invest 2001; 108:1269–1271.
19. Boring L, Gosling J, Cleary M, Charo IF. Decreased lesion formation in CCR2−/− mice reveals a role for chemokines in the initiation of atherosclerosis
. Nature 1998; 394:894–897.
20. Abrass CK. Cellular lipid metabolism and the role of lipids in progressive renal disease. Am J Nephrol 2004; 24:46–53.
21. Gough PJ, Gomez IG, Wille PT, Raines EW. Macrophage
expression of active MMP-9 induces acute plaque disruption in apoE-deficient mice. J Clin Invest 2006; 116:59–69.
22. Li AC, Glass CK. The macrophage foam cell
as a target for therapeutic intervention. Nat Med 2002; 8:1235–1242.
23. Rader DJ, Pure E. Lipoproteins, macrophage
function, and atherosclerosis
: beyond the foam cell
? Cell Metab 2005; 1:223–230.
24. Uitz E, Bahadori B, McCarty MF, Moghadasian MH. Practical strategies for modulating foam cell
formation and behavior. World J Clin Cases 2014; 2:497–506.
25. Diamond JR, Karnovsky MJ. Focal and segmental glomerulosclerosis: analogies to atherosclerosis
Int 1988; 33:917–924.
26. Afkarian M, Sachs MC, Kestenbaum B, et al. Kidney
disease and increased mortality risk in type 2 diabetes. J Am Soc Nephrol 2013; 24:302–308.
27. Groop PH, Thomas MC, Moran JL, et al. The presence and severity of chronic kidney
disease predicts all-cause mortality in type 1 diabetes. Diabetes 2009; 58:1651–1658.
28. Orchard TJ, Secrest AM, Miller RG, Costacou T. In the absence of renal disease, 20 year mortality risk in type 1 diabetes is comparable to that of the general population: a report from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetologia 2010; 53:2312–2319.
29. Go AS, Chertow GM, Fan D, et al. Chronic kidney
disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004; 351:1296–1305.
30. Wen M, Segerer S, Dantas M, et al. Renal injury in apolipoprotein E-deficient mice. Lab Invest 2002; 82:999–1006.
31. Spencer MW, Muhlfeld AS, Segerer S, et al. Hyperglycemia and hyperlipidemia act synergistically to induce renal disease in LDL receptor-deficient BALB mice. Am J Nephrol 2004; 24:20–31.
32. Muhlfeld AS, Spencer MW, Hudkins KL, et al. Hyperlipidemia aggravates renal disease in B6.ROP Os/+ mice. Kidney
Int 2004; 66:1393–1402.
33. Zuo Y, Yancey P, Castro I, et al. Renal dysfunction potentiates foam cell
formation by repressing ABCA1. Arterioscler Thromb Vasc Biol 2009; 29:1277–1282.
34▪. Kennedy DJ, Chen Y, Huang W, et al. CD36 and Na/K-ATPase-alpha1 form a proinflammatory signaling loop in kidney
. Hypertension 2013; 61:216–224.
A unique finding of this study linked a reduction in glomerular foam cell accumulation to improvements in renal function.
35. Tavori H, Fan D, Giunzioni I, et al. Macrophage
-derived apoESendai suppresses atherosclerosis
while causing lipoprotein glomerulopathy in hyperlipidemic mice. J Lipid Res 2014; 55:2073–2081.
36. Wang XX, Jiang T, Shen Y, et al. Diabetic nephropathy is accelerated by farnesoid X receptor deficiency and inhibited by farnesoid X receptor activation in a type 1 diabetes model. Diabetes 2010; 59:2916–2927.
37. Brosius FC 3rd, Alpers CE, Bottinger EP, et al. Mouse models of diabetic nephropathy. J Am Soc Nephrol 2009; 20:2503–2512.
38. Hara S, Kobayashi N, Manabe S, et al. Podocyte injury promotes glomerular lipid peroxidation and foam cell
infiltration under hypercholesterolemia. Presented at the American Society of Nephrology Annual Meeting; November 2014; Philadelphia, PA.
39. Sieweke MH, Allen JE. Beyond stem cells: self-renewal of differentiated macrophages. Science 2013; 342:1242974.
40▪. Robbins CS, Hilgendorf I, Weber GF, et al. Local proliferation dominates lesional macrophage
accumulation in atherosclerosis
. Nat Med 2013; 19:1166–1172.
An important study that challenges a paradigm that circulating macrophages are the main source of lesional macrophages in atherosclerosis, and instead indicates that accumulated macrophages are the result of local proliferation and thereby offers new possibilities for therapeutics.
41. Westerterp M, Murphy AJ, Wang M, et al. Deficiency of ATP-binding cassette transporters A1 and G1 in macrophages increases inflammation and accelerates atherosclerosis
in mice. Circ Res 2013; 112:1456–1465.
42. Sedeek M, Nasrallah R, Touyz RM, Hebert RL. NADPH oxidases, reactive oxygen species, and the kidney
: friend and foe. J Am Soc Nephrol 2013; 24:1512–1518.
43. Holterman CE, Thibodeau JF, Kennedy CR. NADPH oxidase 5 and renal disease. Curr Opin Nephrol Hypertens 2015; 24:81–87.
44. Reidy K, Kang HM, Hostetter T, Susztak K. Molecular mechanisms of diabetic kidney
disease. J Clin Invest 2014; 124:2333–2340.
45. Madamanchi NR, Zhou RH, Vendrov AE, et al. Does oxidative DNA damage cause atherosclerosis
and metabolic syndrome? New insights into which came first: the chicken or the egg. Circ Res 2010; 107:940–942.
46▪▪. Wang Y, Wang GZ, Rabinovitch PS, Tabas I. Macrophage
mitochondrial oxidative stress promotes atherosclerosis
and nuclear factor-(B-mediated inflammation in macrophages. Circ Res 2014; 114:421–433.