Apolipoprotein E–related glomerular disorders

Apolipoprotein E–related glomerular disorders

Journal Pre-proof Apolipoprotein E-related glomerular disorders Takao Saito, Akira Matsunaga, Megumu Fukunaga, Kiyotaka Nagahama, Shigeo Hara, Eri Mus...

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Journal Pre-proof Apolipoprotein E-related glomerular disorders Takao Saito, Akira Matsunaga, Megumu Fukunaga, Kiyotaka Nagahama, Shigeo Hara, Eri Muso PII:

S0085-2538(19)31145-7

DOI:

https://doi.org/10.1016/j.kint.2019.10.031

Reference:

KINT 1865

To appear in:

Kidney International

Received Date: 7 August 2019 Revised Date:

25 October 2019

Accepted Date: 28 October 2019

Please cite this article as: Saito T, Matsunaga A, Fukunaga M, Nagahama K, Hara S, Muso E, Apolipoprotein E-related glomerular disorders, Kidney International (2019), doi: https://doi.org/10.1016/ j.kint.2019.10.031. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Copyright © 2019, Published by Elsevier, Inc., on behalf of the International Society of Nephrology.

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Review Article (KI(KI-0707-1919-1082.R 1082.R2 .R2 clean) Apolipoprotein EE-related glomerular disorders

Takao Saito1,2, Akira Matsunaga3, Megumu Fukunaga4, Kiyotaka Nagahama5, Shigeo Hara6, Eri Muso7,8 1Sanko

Clinic, Fukuoka, Japan; 2Faculty of Medicine, Fukuoka University, Fukuoka,

Japan; 3Department of Laboratory Medicine, Faculty of Medicine, Fukuoka, Japan; 4Toyonaka

Keijinkai Clinic, Toyonaka, Japan;

5Department

of Pathology, Kyorin

University School of Medicine, Tokyo, Japan; 6Department of Diagnostic Pathology, Kobe City Medical Center General Hospital, Kobe, Japan; 7Division of Nephrology and Dialysis, Kitano Hospital, Osaka, Japan; 8Department of Food and Nutrition, Faculty of Contemporary Home Economics, Kyoto Kacho University, Kyoto, Japan

Correspondence: Correspondence: Takao Saito, Sanko Clinic, 4-9-3 Ropponmatsu Chuoku, Fukuoka

810-0044, Japan. E-mail: [email protected]

Running headline ApoE-related glomerular disorders

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Abstract Abstract Of the glomerular disorders that occur due to apolipoprotein E (apoE) mutations, apoE2 homozygote glomerulopathy and lipoprotein glomerulopathy (LPG) have been identified. ApoE2 homozygote glomerulopathy was found in individuals expressing homozygous apoE2/2. This was characterized histologically by glomerulosclerosis with marked infiltration of foam cells derived from macrophages and, occasionally, with non-lamellated lipoprotein thrombi. Recently, several cases of apoE Toyonaka (Ser197Cys) combined with homozygous apoE2/2 have been reported, where non-immune

membranous

nephropathy-like

features

observed

in

glomeruli.

Interestingly, in these cases, apoE accumulation was identified by tandem mass spectrometry. Therefore, it is speculated that these findings may arise from apoE molecules without lipids, which result from hinge damage by apoE Toyonaka and may cross the glomerular basement membrane as small molecules. LPG is primarily associated with heterozygous apoE mutations surrounding the LDL-receptor binding site, and it is histologically characterized by lamellated lipoprotein thrombi that lack foam cells. Recent studies have suggested that LPG can be induced by thermodynamic destabilization, hydrophobic surface exposure and the aggregation of apoE resulting

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from the incompatibility of apoE mutated residues within helical regions. Additionally, apoE5 may play a supporting role in the development of LPG and in lipid-induced kidney diseases via hyperlipoproteinemia. Thus, it is interesting that many apoE mutations

contribute

to

characteristic

glomerular

disorders

through

various

mechanisms. In particular, macrophages may uptake lipoproteins into the cytoplasm and contribute to the development of apoE2 homozygote glomerulopathy as foam cells, and their dysfunction may participate in the accumulation of lipoproteins in the glomerulus causing lipoprotein thrombi in LPG. (250words)

Key words: apolipoprotein mutations, apolipoprotein E2 homozygote glomerulopathy, lipoprotein glomerulopathy, apolipoprotein E Toyonaka, apolipoprotein E5, macrophage (Word count of text including abstract: 3981)

Introduction To explain the relationship between lipid abnormalities and chronic kidney disease, Moorhead et al.1 proposed the hypothesis of lipid nephrotoxicity in 1982. Additionally, Farragiana and Churg2 pathologically reviewed renal lipidoses and found that abnormal lipid storage in a number of diseases occurred either due to an inborn error in

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metabolism or as a consequence of complex metabolic alterations. Few studies, however, have provided clear evidence regarding the causal relationship between abnormal lipid metabolism and renal disorders. Meanwhile, various glomerular disorders caused by abnormalities in apolipoprotein E (apoE) composing-lipoproteins have recently been identified. Therefore, these disorders should be investigated to elucidate the mechanisms of pathological condition related to abnormal lipid metabolism in the kidney. In this review, we would like to introduce the apoE-related glomerular disorders that have been reported so far and outline the role of various apoE abnormalities in these disorders.

ApoE Apolipoprotein molecules bind to lipids, form lipoproteins and are involved in lipoprotein metabolism as lipids transport proteins, ligands possessing chylomicron remnants and low-density lipoprotein (LDL) receptors and coenzymes that activate lipid-related enzymes3. In particular, apoE composes very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL) and high-density lipoproteins (HDL) together with triglyceride and cholesterol, and this protein possesses a central role in the metabolism of lipoproteins within the blood4. It is known that apoE-related

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lipoprotein abnormalities occur not only in cardiovascular diseases but also in various neurological and infectious diseases5. Additionally, several renal diseases associated with apoE mutations have been described, and the function and role of apoE within the kidney has been studied. ApoE is a glycoprotein composed of 317 amino acids, and it is coded by a gene on chromosome 19. A signal peptide of 18 amino acids at the N-terminus is diverged, and a mature protein of 299 amino acids (molecular weight: approximately 34,000) is secreted extracellularly4,5 (Fig. 1). 1) ApoE can be separated primarily into two domains, each possessing a different structure and function5,6. The N-terminal domain (amino acids 1 to 191) consists of four α-helices including an LDL-receptor binding region (amino acids 136 to 150) and a heparan sulfate proteoglycans (HSPG) binding region (amino acids 142 to 147). The C-terminal domain, composing one third of the apoE molecule (amino acids 216 to 299), is critical for lipid binding. In particular, residues within the regions of amino acids 244 to 272 form amphipathic α-helices that mediate the binding of apoE to lipoprotein. Additionally a protease-sensitive loop within the hinge region (amino acids 192 to 215) may play an indispensable role in the binding of both domains6 (Fig. 1). 1)

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The human APOE gene has three alleles (ε2, ε3 and ε4), and these are expressed as the apoE isoforms E2, E3 and E4, respectively4,5. ApoE3 is the most common isoform present in more than 70% of the general population. Compared to the amino acid residues of apoE3, a cysteine is substituted for arginine at position 158 in apoE2, and an arginine for cystein at position 112 in apoE4. ApoE17, apoE5 and apoE78 are known as minor isoforms and possess several variants with different amino acid substitutions. In particular, apoE5 is known to be involved in kidney damage and will be discussed later (see “ApoE5 involvement”). ApoE3 carriers are typically normolipidemic, although apoE4 is a risk factor for Alzheimer’s disease5, and apoE2 homozygosity occasionally induces type III hyperlipoproteinemia (HLP) as a result of its inability to bind to the LDL receptor9. ApoE is a multifunctional protein that is synthesized primarily within the liver. However, it is also synthesized in several other tissues and cell types including the brain, kidney, adipocytes and macrophages10. This protein serves as a ligand for the receptor-mediated uptake of lipoproteins and plays a key regulartory role in the clearance of lipoproteins from the plasma. In the brain, apoE is generated in astrocytes and glia cells and is assembled in the lipoproteins of cerebrospinal fluid. Various functions of the central nervous system are related to apoE, and Alzheimer's disease

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associated with apoE4 may occur due to the failure of one or more of these functions5. The amount of apoE derived from macrophages is small but sufficient to reduce atherosclerosis without lowering hypercholesterolemia11,12. It is important to elucidate these functions when considering the role of apoE in the renal lesions associated with macrophages13.

ApoEApoE-related glomerular diseases

glomerulopathy.. ApoE2 homozygote glomerulopathy

In 1974, Amatruda et al.14 detailed

glomerular lesions with foam cells in a case of type III HLP. Thereafter, the apoE2 homozygocity was determined as responsible for type III HLP, and 10 cases exhibiting glomerular lesions due to this apoE isoform were reported worldwide15-21. Kawanishi and colleagues21 summarized these cases as apoE2 homozygote glomerulopathy in a review article. The histological features of these cases are glomerulosclerosis with marked foamy macrophage infiltration (Fig. 2a) and it is often difficult to differentiate from diabetic nephropathy when accompanied by diabetes mellitus. As some patients do not necessarily suffer from diabetes mellitus, however, it is conceivable that abnormal lipidosis with type III HLP causes glomerular lesions characterized by foamy macrophages.

This

pathology

can

be

explained

through

the

concept

of

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glomerulosclerosis, as suggested by Diamond and Karnovsky22, who applied the mechanism of atherosclerosis to kidney disease in the 1980s. As reported by Sakatsume

et al.20, however, some cases of apoE2 homozygote glomerulopathy displayed lipoprotein thrombi

or non-immune subendothelial and subepithelial electron dense deposits

(EDD), although lamella formation was not detected in lipoprotein thrombi as it was those in lipoprotein glomerulopathy (LPG). Considering that apoE2 homozygote glomerulopathy is based on type III HLP with increased serum triglycerides, VLDL and IDL, it is speculated that apoE2 is specifically involved in glomerular lesions possessing lipoprotein thrombi without lamella influenced by type III HLP, and this occurs in addition to the mechanism of atherosclerosis by LDL cholesterol. Indeed, two papers

reported the relationship between heterozygous apoE2 and characteristic findings as follows. One case with apoE2/323 was associated with marked non-immune subendothelial EDD. The other case24 had the combination of heterozygous apoE2 and apoE Tokyo/Maebashi25,26 isoforms and showed infiltration of foamy macrophages in addition to lipoprotein thrombi. As apoE Tokyo/Maebashi25,26, an in-frame deletion of Leu141 to Lys143, is one of the representative mutations for LPG, atypical histopathological changes may be induced by a compound heterozygote.

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Several studies indicated that the apoE2 isoform was a significant risk factor for the development of diabetic nephropathy in both type 127-29 and type 230-34 diabetes, although papers opposing such a relationship were also presented.35-39 Therefore, it is likely that diabetic nephropathy is influenced by abnormal lipid metabolism via apoE240. Additionally, Yorioka et al.41 reported that serum apoE2 levels were correlated with the severity of IgA nephropathy, and some studies42,43 suggested that the apoE2 allele may be involved in the progression to end-stage renal disease. In contrast, the proportion of apoE2 homozygote carriers is 0.5 to 1% within the entire population, and in these carriers, type III HLP is found in less than 10% of individuals. Additionally, as reports of apoE2 homozygote glomerulopathy are limited to 10 cases in the world, specific etiological factors other than the apoE2 homozygote may conribute to the development of this disease21.

nephropathy--like apoE deposition d diisease (MN (MN--like apoE disease) disease).. Membranous nephropathy Recently, a new glomerular disease was identified in non-consanguineous carriers possessing the combination of apoE Toyonaka (Ser197Cys), a novel mutation, and apoE2 homozygote44-46 (Fig. 1). 1) The first case reported by Fukunaga et al.44 was a 20-year-old Japanese female patient who underwent renal biopsy because she was found to have chance proteinuria and hematuria. In silver-methenamine-stained

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sections of a biopsy specimen, “spike” formation as seen in membranous nephropathy (MN) was found in the majority of glomeruli without mesangial proliferation or matrix expansion (Fig. 2b). 2b) Electron microscopy (EM) revealed massive EDD located primarily in the subepithelial area of the glomerular basement membrane (GBM) and also in the subendothelial and mesangial areas (Fig. 3a). 3a) These findings were similar to those observed in secondary MN associated with autoimmune disease, for example lupus nephritis type V, rather than idiopathic MN. The appearance of microbubbles or microcysts appearances on higher magnification EM images (Fig. 3b) and non-specific IgG and C3 depositions in the immunofluorescence study, however, refuted the immunogenicity of this disease. Meanwhile,

glomerular

apoE

accumulation

was

identified

by

immunohistochemical studies (Fig. 3c) and tandem mass spectrometry, and the apoE levels were determined to be extremely high in the serum, although hyperlipidemia was not identified. These findings suggested the involvement of apoE mutation in this disease, and analysis of the apoE gene detected apoE Toyonaka (Ser197Cys) in the hinge region of one allele in combination with apo E2 homozygosity (Fig. 3d). 3d) Other than several non-invasive single-nucleotide polymorphisms (SNPs)47, mutations in the hinge region have not yet been reported. Therefore, apoE Toyonaka

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may be the first mutation within the hinge region that plays a pathological role in apoE-related

diseases.

A deformed

hinge

region

may

markedly

affect

the

three-dimensional structure of apoE and cause disconnections not only between the N-terminal domain and LDL receptors but also between the C-terminal domain and lipids. This is likely due to the observation that the structural and functional stability of apoE is mediated by the hinge region connecting both terminals48-50. When apoE Toyonaka is involved in hinge damage, type III HLP induced by defective binding to the LDL receptor in the N-terminal domain of the apoE2 homozygote may be negated due to the dysfunction of the C-terminal domain that connects with lipids. In contrast, altered apoE without lipids may accumulate within the glomerulus and induce EDD in the subepithelial region, as the apoE molecule is relatively small (34 kDa) and rich in

arginine, a positively-charged amino acids4 that may cross GBM. Thus, it is speculated that apoE Toyonaka may play a pivotal role in nonimmune MN-like lesions with spike formation. The other two cases exhibiting apoE Toyonaka and apo E2 homozygosity45,46 were

of type III HLP with marked hypertriglyceridemia, which was different from the case presented by Fukunaga et al.44 The serum apoE levels, however, were high in all three cases. Spike formation was recognized by light microscopy, and subepithelial and

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subendothelial EDD including microbubbles were both observed by electron microscopy. Immunoglobulin and complement depositions were not specifically obsereved in immunofluorescence studies. Unlike the case reported by Fukunaga et al.44, foam cells characteristic of apoE2 homozygote glomerulopathy and non-lamellated lipoprotein thrombi as reported by Sakatsume et al.20 were conspicuous in the cases reported by Hirashima et al.45 and Kato et al.46, respectively. Therefore, in carriers exhibiting both apoE2 homozygote and apoE Toyonaka, the balance of nonimmune MN-like lesions and apoE2 homozygote glomerulopathy may be dependent upon the influence of apoE Toyonaka within the hinge region.

ipop (LPG).. LPG was identified as a glomerular disease Lipo protein glomerulopathy (LPG) associated with type III HLP in 198951. The genetic and pathological features, however, differ from those of apoE2 homozygote glomerulopathy. As we have previously described this disease in several reviews and commentaries40,52-58, we will only briefly introduce the overview and recent studies in this section. In contrast to apoE2 homozygote glomerulopathy, this disease was characterized by dilated glomerular capillaries with lipoprotein thrombi showing lamella formation instead of foam cells40 (Fig. 2c). 2c) Similar cases were thereafter reported from some areas in Japan59-61, and they were categorized into a single disease entity62. Through apoE gene analyses, various mutations were

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discovered in patients suffered from LPG25,26,63-77 (Fig. 1). 1). Although most were heterozygous apoE missense variants close to the LDL receptor binding site63-73, mutants far from the LDL receptor binding site74-75 or involving the deletion of several amino acids25,26,76,77 were also reported. Additionally, Ishigaki et al.78 revealed that the virus-mediated transduction of apoE Sendai, first reported in human LPG, reproduced LPG-like lesions in the kidney of experimental apoE-knock out mice. Although Wen et

al.79 reported that aged apoE knock-out mice spontaneously developed LPG and that apoE Sendai was not necessarily required for onset of LPG, Ishimura et al.80 clearly demonstrated lipoprotein thrombi in LPG induced by apoE Sendai, deferentiated those from the lesions in aged mice and clarified that apoE Sendai was responsible for the oncet of LPG. Approximately 150 LPG cases have been reported worldwide54, where most are from Japan and China; however, there are also cases from the USA, Italy, France, Brazil and Russia. Recent in depth studies suggest that the incidence of APOE Sendai and APOE Kyoto, the major LPG mutants, have increased through a founder mutation in Japan81 and China82, respectively. It is interesting, however, that LPG cases with apoE Sendai are restricted to eastern Japan. In contrast, cases possessing apoE Kyoto are found worldwide, in Asia, the United States and European countries56.

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At the time of its discovery, type III HLP was considered to be prominently involved in LPG as well as in apoE2 homozygote glomerulopathy. Currently, however, the apoE structural deformities caused by apo E mutations are considered to be direct risk factors that contribute to the onset of LPG as normolipidemic cases are occasionally reported25,52. In particular, the majority of the apoE mutants associated with LPG including apoE Sendai possess the substitutions of proline for arginine63,65,68,70-72, as this mutation loosens the α-helix structure and transforms the LDL receptor binding site (residues 140-150). From this perspective, Hoffmann et al.83 demonstrated a reduction in receptor binding activity of apoE Sendai. Additionally, Georgiadou et al. in Greece84 suggested in their detailed biochemical analysis that LPG could be induced by thermodynamic destabilization, hydrophobic surface exposure and aggregation of apoE resulting from the incompatibility of proline within helical regions. Meanwhile, in apoE Kyoto, a point mutation is different from LDL-receptor binding site and does not appear to be involved in the reduced binding to LDL receptor. Matsunaga et al.74, however, demonstrated that apoE Kyoto exhibits only 10% of the normal receptor-binding activity in an in vitro competition assay using apoE lysosomes. Furthermore, a recent study by a Greek group85 suggested that the non-proline substituted apoE mutants assoociated with LPG including apoE Kyoto may also

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contribute to protein aggregation within glomerular capillaries and that a common underlying mechanism may be responsible for the pathogenesis of LPG.

involvement.. ApoE5, one of the minor isoforms of apoE, is detected at a ApoE5 involvement more positive charge compared to that of apoE4 in response to isoelectric focusing. Genetically, several variants have been reported worldwide, where apoE5 (Glu3Lys) alone is observed at a relative frequency of approximately 0.1% within the total Japanese population8 (Fig. 1). 1) Interestingly, it has been postulated that carriers of apoE5 are at risks for hyperlipidemia and subsequent atherosclerosis, despite exhibiting a two-fold greater LDL receptor-binding activity than that of wild type apoE3 carriers86. To explain this paradox, it has beens suggested that hypercholesterolemia results from the down regulation of LDL receptor due to the high uptake of apoE5-containing lipoproteins86. Few studies exist, however, regarding apo E5 in this century, and the precise mechanism underlying its function remains unclear. The first renal disease associated with apoE5 was reported in a transplant case with LPG87. LPG was diagnosed from renal biopsy of the original kidney59 and this ultimately developed into end-stage renal disease. The patient underwent a cadaver renal transplant, and the relapse of LPG was observed at the 1 year follow-up biopsy. Miyata et al.87 identified heterozygous apoE mutations with apoE2 and apoE5

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(Glu3Lys) in this patient. In contrast, Kodera et al.88 recently reported another case of LPG that possessed apoE Chicago and apoE5 (Glu3Lys), and they clarified, by gene analysis of the family of the patient, that both mutations were expressed within the same allele. Additonally, apoE Chicago was also identified in a re-analysis88 of the case previously analyzed by Miyata et al.87. Takasaki et al.89 also reported a case of LPG possessing a combination of apoE Sendai and apoE5 (Glu3Lys). Thus, the occurrence of LPG cases with heterozygous apo E5 appears to be increasing, and all of these cases exhibit hypertriglyceridemia of 400 mg / dL or greater59,88,89. It is unknown if apoE5 plays a pathogenetic role in LPG, as apoE5 in these cases has always been associated with LPG-specific mutants such as apoE Chicago or apoE Sendai. Hypertriglyceridemia resulting from apoE5, however, is likely to be the trigger for LPG. In contrast, we have observed focal and segmental glomerulosclerosis (FSGS) with apoE5(Glu3Lys)/E390 (Fig. 2d), 2d) that displays hypercholesterolemia and foamy macrophages. As the etiological role of hyperlipidemia in FSGS has been studied experimentally91,92 and clinically93, it is possible that apoE5(Glu3Lys)-induced hyperlipidemia is involved in the development of FSGS as shown in the next section. . Collectively, these findings indicate that apoE5 may be one of the risk factors underlying lipid-induced kidney diseases.

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Role of Macrophag Macrophage Ever since the speculation by Brown and Goldstein94 regarding the mechanisms underlying atherosclerosis, the role of macrophage infiltration associated with endothelial injury, hyperlipoproteinemia and hypertension have been discussed in the context of FSGS and other glomerular diseases95. Indeed, we have demonstrated that macrophages are increased in experimental and clinical FSGS92,93 and in diabetic glomerulosclerosis96. For apoE-related glomerular diseases, similar findings were observed in apoE2 homozygote glomerulopathy, and a case of FSGS that was associated with apoE590 also illustrated the significance of macrophage infiltration due to hyperlipoproteinemia as mentioned above. In contrast, foamy macrophage infiltration is rarely observed in LPG, and lipoprotein thrombi due to the accumulation of lipoprotein is one of diagnostic criteria40. Kanamaru et al.97 found that LPG-like glomerular lesions with lipooprotein thrombi were induced by graft-versus-host disease in Fcγ receptor (FcRγ)-knockout mice possessing normal apoE, and they suggested that these findings resulted from the decrease of LDL uptake in macrophages. This speculation was later confirmed by an additional experiment using a similar model, that showed a drastic decline of scavenger receptors CD3698. Additionally, Ito et al.99 generated LPG-like lesions in apoE and FcRγ

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double knockout mice through the injection of various vectors of apoE mutants and they revealed that the impairment of macrophage plays a prominent role in the development of LPG associated with apoE abnormalities. In addition to these experiments, some studies exist showing that macrophages produce a small amount of apoE, that is important for the suppression of hyperlipidemia and arteriosclerosis11-13. Interestingly, one of these studies showed that the expression of macrophages producing apoE Sendai in mice that received bone marrow transplant protected against atherosclerosis while inducing LPG13. Collectively, these results indicate that macrophages play various roles in lipoprotein metabolism involving apoE, and that their hyperactivity or suppression can be an important factor in each different type of renal lipidosis. In particular, as carriers with apoE mutants of apoE2 homozygote glomerulopathy21 and LPG81,82 show low genetic penetrance, the functional variety of macrophages may be important as another etiological

factor

of

these

diseases57.

Additionally,

it

is

of

interest

that

macrophage-derived apoE may be associated with mutations and may regulate the activity of these diseases13 (Fig. 4). 4) Further studies, however, are needed to clarify these findings.

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Treatments Treatments and Prognosis As described above, apoE-related glomerular diseases are caused by lipoprotein degeneration based on apoE gene mutations, even if pathological types are different, and often they progress into end-stage renal disease. Accordingly, no suitable treatment has been recognized at present. LPG, however, is typically associated with type III HLP, where triglyceride-rich lipoproteins such as VLDL and IDL, are the major components, and our studies have clarified that hypertriglyceridemia exacerbates LPG in human cases54,100 and in animal models78,99. From this perspective, the prevention of hypertriglyceridemia may be important in LPG treatment, and the efficacy of lipid-lowering agents including fibrates has been clinically and pathologically reported in several cases in Japan66,88,101-103. Additinally, Hu et al.82 compared patient and renal survival rates over 3 years between fenofibrate-treated and control groups and they confirmed the significant availability of fenofibrate for LPG treatment. In contrast, in apoE2 homozygote glomerulopathy, fibrates have been used in some cases but the effect is unclear21. In advanced chronic kidney disease (CKD), triglyceride-rich lipoproteins including VLDL and IDL are increased in a manner similar to that observed in LPG regardless of the origin of CKD104. This observation suggests that lipid-lowering treatment with fibrates in LPG may provide insights on the prevention of renal

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dysfunction in CKD, as pemafibrate, a selective peroxisome proliferator-activated receptor-α modulator, exhibited an effective safety profile and efficacy in patients with CKD105. Although apheresis therapy has been attempted in some cases of LPG, its effect is unclear. Interesting case reports from Italy106 and China107 have been useful when discussing the mechanism of LPG. In an Italian case106, apheresis was performed using a heparin-induced extracorporeal lipoprotein precipitation (HELP) system instead of the usual LDL-apheresis with dextran sulfate columns to avoid anaphylactoid reaction to ACE inhibitors, and thus treatment approach led to complete remission within a very short time. The authors suggested that heparin in HELP activated lipoprotein lipase and hepatic triglyceride lipase and easily removed triglyceride-rich lipoproteins, such as VLDL and IDL, that were generally elevated in LPG. In China107, 13 patients with LPG were treated with staphylococcal protein-A immunoadsorption. As a result, a rapid decline in urine protein and serum apoE levels, with the disappearance of LPT in a repeat biopsy, was observed. As protein-A possesses strong affinity to the Fc portion of IgG and acts as an FcRγ, this effect may compensate for FcRγ deficiency as studied in rat LPG by Kanamaru et al97 and may lead to the improvement of LPG.

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Renal transplantation has been performed in several cases of LPG, but recurrence is recognized in most of them, as indicated in the previous reports87,108-110 and reviews40,52. The apoE abnormality in each recipient may induce lipoprotein thrombi in the transplanted kidney.

Conclusions Conclusions ApoE is an important apolipoprotein that plays a central role in lipoprotein metabolism. Abnormal lipoprotein metabolism caused by apoE mutations is involved in variety of disorder. Among these, from the perspective of kidney diseases, there are several notable pathological conditions (Table 1), 1) and these conditions can be categorized into apoE-related glomerular disorders. Meanwhile, recent studies have revealed that the hyperactivity and suppression of macrophages, in addition to apoE mutations, are involved in these disorders. Thus, it must be considered that various factors other than apoE mutations are responsible for their development. There are many unresolved problems, however, and future research in this field must be expanded..

DISCLOSURE All authors declare no competing interests.

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ACKNOWLEDGMENTS The authors thank Drs. Kenichi Kudo, Shinichi Oikawa, Hiroshi Sato, Hisako Hirashima, Toshiyuki Komiya, Tamayo Kato, Satoshi Takasaki, Hitoshi Kodera, Kenji Ito and Maho Watanabe for their collaboration, and we also thank members of the Japanese Society of Kidney and Lipids for their warm support.

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Figure legends

Figure 1. Structure and representative mutations of apoE. Underlined mutants other than apoE4 are associated with glomerular disorders (see text). del, deletion of amino acid residues. Figure 2. Representative glomerular findings by light microscopy. (a) ApoE2 homozygote glomerulopathy (Azan-Mallory staining). (b) Membranous nephropathy-like apoE deposition disease (Silver-methenamine staining). (c) Lipoprotein glomerulopathy (Masson’s trichrome staining). (d) Focal and segmental glomerulosclerosis with apoE5(Glu3Lys)/E3 (Periodic acid-Shiff staining). Figure 3. Characteristic findings of membranous nephropathy-like apoE deposition disease. (a) Electron microscopy revearls highly electron dense deposits mainly in the subepithelial area. (b) At larger magnification, these electron dense deposits consist of microbubbles or microcysts. GBM, glomerular basement membrane. (c) Immunochemical staining shows apoE-positive deposits particularly within the subepithelial areas (arrows).44 Reprinted with permission from Fukunaga M, Nagahama K, Aoki M, et al. Membraonous nephropathy-like apolipoprotein E deposition disease with apolipoprotein

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E Toyonaka (Ser197Cys) and a homozygous apolipoprotein E2/2. Case Rep Nephrol Dial. 2018;8:45-55. Copyright © 2018 S. Karger AG. (d) DNA sequence analysis of the APOE gene reveals that a heterozygous missense mutation in exon 4 leads to amino acid substitution Cys (TGC, lower) for Ser (TGC, upper) at codon 197 within the hinge region together with a homozygous apo E2 (Arg158Cys) mutation. Figure 4.

Role of macrophage in apoE2 homozygote glomerulopathy and LPG.

The characteristics of apoE2 homozygote glomerulopathy and LPG depend upon hyperactivity and suppression of macrophages themselves, respectively. In contrast, as the dotted lines indicate, apoE derived from macrophages may be affected by its mutation to regulate each disease activity.

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Table 1

ApoE phenotypes

ApoE phenotypes and glomerular disorders

Patterns of dyslipidemia

Glomerular disorders Name

ApoE2/E2

Type III HLP

ApoE2 homozygote glomerulopathy

References

Characteristics

Foamy macrophages,

21

Gglomerulosclerosis, Occasional EDD

ApoE2/E2

Normolipidemia

MN-like apoE

Spike formation,

44-46

+ApoE Toyonaka(Ser197Cys)

or Type III HLP

deposition disease

ApoEa/E3 or E4

Mostly type III HLP

LPG

Lipoprotein thrombi

57, 58

ApoE5(Glu3Lys)/apoEb

Type III HLP

LPG

Lipoprotein thrombi

87-89

ApoE5(Glu3Lys)/apoE3

Hypercholesterolemia

FSGS

Foamy macrophages,

90

Subepithelial EDD

Glomerulosclerosis

apoE, apolipoprotein E; type III HLP, type III hyperlipoproteinemia; EDD, electron dense deposits; MN, membranous nephropathy; LPG, lipoprotein glomerulopathy; FSGS, focal and segmental glomerulosclerosis. a

Fifteen novel apoE variants specific for LPG have been reported so far.

b

ApoE2, apoE Chicago and apoE Sendai have been reported as another isoform of apoE5(Glu3Lys).

E5(Glu3Lys)

NH2

Glu

20

Arg

E-Kyoto (Arg25Gys)

40

80

100

E4(Cys112Arg)

60

Val

Cys Gly Leu Gln Arg 120 Gln Arg Val Ala Leu Tyr Gly Val E-Tsukuba (Arg114Cys) Gly Met Glu Gin LDL-receptor binding site E-Tokyo/Maebasi (del 141-143/142-144) Ser E-Okayama (Arg150Gly) E-Chicago (Arg147Pro) Thr 130 Arg Arg Ala Arg 150 Lys Asp Leu Arg Arg Lys Leu Ser Leu Val Leu Glu Glu Arg Leu Leu His Ala 140 Asp E-Sendai (Arg145Pro)

N-terminal domain 1-191

Asp Gin Arg Ala Tyr Ala Ala Glu Gly Ala Glu Leu Lys Leu Val Gln Gly Arg Arg 160 E2(Arg158Cys) Gly 173 E1(del 156-173) 220

200

Hinge region 192-215

Ser

197

E-Toyonaka(Ser197Cys) 240

260

280

COOH

C-terminal domain 216-299

Foam cells and glomerulosclerosis ApoE2 homozygote glomerulopathy

Down-regulation Hyperactivity Expression

APOE mutations

Secretion

Abnormal lipoproteins

Macrophages Suppression

ApoE Up-regulation Lipoprotein glomerulopathy

Lipoprotein thrombi