Clin Exp Nephrol DOI 10.1007/s10157-013-0887-4
REVIEW ARTICLE
WCN 2013 Satellite Symposium ‘‘Kidney and Lipids’’
Topics in lipoprotein glomerulopathy: an overview Takao Saito • Akira Matsunaga • Kenji Ito Hitoshi Nakashima
•
Received: 29 September 2013 / Accepted: 3 October 2013 Ó Japanese Society of Nephrology 2013
Abstract Here, we introduce four topics in lipoprotein glomerulopathy (LPG). To date, approximately 150 cases of LPG have been reported worldwide. Recently two groups studied hot spots of APOE-Sendai and APOEKyoto, the representative variants of LPG, in narrow areas of Japan and China, respectively. They suggest that both variants have descended through a founder effect. APOESendai and APOE-Kyoto cause different transformations of apolipoproteins aggregating lipoproteins and resulting in lipoprotein thrombi within the glomerulus. Moreover, the macrophage impairment in LPG may provide another mechanism for lipoprotein thrombi in which massive lipoproteins accumulate in the glomerulus without foam cells. On the other hand, the administration of fibrate with the intensive control of triglyceride and apolipoprotein E particularly from the early phase will ameliorate LPG and prevent renal dysfunction. Keywords Founder effect ApoE transformation Macrophage impairment Fibrate
T. Saito (&) General Medical Research Center, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan e-mail: [email protected] A. Matsunaga Department of Laboratory Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan K. Ito H. Nakashima Division of Nephrology and Rheumatology, Department of Internal Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
Introduction The concept of lipoprotein glomerulopathy (LPG) was first discussed in the Annual Meeting of the Japanese Society of Nephrology in 1988 on the basis of five cases, and published in 1989 by both our group [1] and Watanabe et al. [2]. At the time of discovery, extremely dilated glomerular capillaries filled with huge lipoprotein-rich materials called lipoprotein thrombi were histologically characteristic. Clinically, proteinuria was sometimes mild but progressed to nephrotic syndrome in most cases [3]. Dyslipidemia generally classified into type III hyperlipoproteinemia was marked and associated with high serum apolipoprotein E (apoE) levels [4], although no systemic manifestations related to lipidosis, such as corneal opacity, xanthoma striata palmaris or other xanthomas, were observed. Moreover, the familial occurrence of LPG has been frequently recognized, and heterozygous novel APOE variants, that is, APOE-Sendai and APOE-Kyoto, were identified in the cases of LPG by Oikawa et al. [5] and Matsunaga et al. [6] in 1997 and 1998, respectively. Therefore, we believe that LPG is an inherited disease in which abnormal lipoproteins composed of apoE mutants accumulate within the glomerulus. However, asymptomatic carriers with such mutants have demonstrated the low genetic penetrance and suggested other etiological factors concerned with LPG. Recent clinical and experimental studies have produced valuable results and elucidated the pathogenic mechanisms and useful treatments. We discuss topics related to these matters here.
Distribution of LPG cases and the founder effect To date, approximately 150 cases of LPG have been reported worldwide. These cases were mainly in East Asia,
123
Clin Exp Nephrol Table 1 Analyzed DNA sequences of lipoprotein glomerulopathy by country APOE mutation
Japan
APOE-Sendai
25
APOE-Kyoto
6
APOE-Tokyo/Maebashi
2
APOE-Guanzhou APOE-Chicago APOE-Osaka/Kurashikio
China
Hong Kong
Taiwan
USA
France
Italy
Total
0
0
0
0
0
0
25
39
0
1
2
1
0
49
5
0
0
0
0
0
7
0
4
0
0
0
0
0
4
2
0
0
0
1
0
0
3
2
0
0
0
0
0
0
2
APOE2 (Classic)
2
0
0
0
0
0
0
2
Other APOE mutations*
5
0
1
0
1
0
1
8
No APOE Mutation
0
17
0
0
0
0
0
17
44
65
1
1
4
1
1
117
Total
* APOE-Tsukuba, APOE-Okayama, APOE-Kanto, APOE1(del 156–173), APOE5(Glu3Lys), APOE-Hong Kong, APOE-Las Vegas and APOEModena (one case each)
including Japan and China, but several were also seen in Europe and the United States [3]. After the discoveries of apoE-Sendai (Arg145Cys) in 1997 [5] and apoE-Kyoto (Arg25Cys) in 1998 [6], which are specific for LPG, DNA sequence analysis of the APOE gene has been recognized as the most important tool for identifying the diagnostic criteria of LPG [3]. To our knowledge, this testing was conducted in 117 cases of LPG [7] (Table 1). The polymorphism of the APOE mutation in LPG is clearly established since the identification of 15 novel APOE variants. However, the histological findings and clinical manifestations seem to be common among patients with different APOE variants. ApoE-Sendai, a major variant, was limited in patients who lived in east Japan, particularly in a narrow area lying across Yamagata and Miyagi prefectures. From this point of view, Toyota et al. [8] investigated the haplotype of APOE-Sendai in 13 Japanese patients with LPG from nine unrelated families and suggested that the APOE-Sendai mutation is common in Japanese patients through a founder effect. In contrast, APOE-Kyoto, the other major variant, has been distributed throughout the world. Namely, this mutation was found in not only among Asians in Japan, China and Taiwan but also among Caucasians in Europe and the United States [7]. Recently, Hu et al. [9] detected a hot spot of LPG with APOE-Kyoto in a narrow area of the Sichuan Basin, China, and investigated the genetic and clinical features of 35 patients with LPG and 28 asymptomatic carriers in 31 families. Their in depth and detailed study findings also suggest that the descent of APOE-Kyoto in this area was derived from a single founder. Accordingly, it is of interest that the incidence of APOE-Sendai and APOE-Kyoto, the major LPG mutants, may both have increased through a founder effect. However, the connection of APOE-Kyoto between Sichuan Basin and other areas cannot be easily explained unless the haplotypes of
123
APOE-Kyoto are compared worldwide. Of course, it may be possible that APOE-Kyoto spread worldwide from China because it is historically known that the international exchange of Chinese people has been popular from ancient times compared to that of Japanese people who are surrounded by the sea. This theory may be similar to the fact that tea culture expanded worldwide from China. Several other APOE variants have recently been reported in Europe and the United States as well as in Asia. Other hot spots of APOE variants associated with LPG may be detected across the world.
ApoE structure and glomerular injury Apart from the influence of type III hyperlipoproteinemia that is usually found in LPG, the apoE structural deformities that result from APOE mutations may play a pivotal role in the development of lipoprotein thrombi in the glomerulus. In particular, substitutions of proline for arginine in apoESendai, apoE-Chicago, apoE-Guangzhou and apoE-Osaka/ Kurashiki loosen the a-helix structure and transform the low-density lipoprotein (LDL)-receptor binding site in apoE. In this point of view, Hoffmann et al. [10] suggested that apoE-Sendai revealed reduction of receptor binding activity. Recently, Georgiadou et al. [11] have discovered in their detailed biochemical analysis that these mutations induce significant folding defects that extend to the whole N-terminal domain of the protein. They also mentioned that these findings provide novel mechanistic insight for the role of these mutants in the pathogenesis of LPG. Meanwhile, in apoE-Kyoto, a mutant point differs from an LDL-receptor binding domain and may not be involved in the binding defect of the LDL receptor. However, in an in vitro competition assay using apoE lysosomes, Matsunaga et al. [6] showed that apoE-Kyoto has only 10 % of the normal receptor-binding activity. Moreover, it is
Clin Exp Nephrol
Fig. 1 Comparison of the pathogenesis of lipoprotein glomerulopathy and hypercholesterolemic glomerulosclerosis (hypothetic)
possible that the residue of cysteine 25 is exposed on the surface of apoE and form a disulphide bridge with the other cysteine residue resulting in the large aggregation of apoE [12]. These findings also suggest the mechanism of lipoprotein thrombi in the glomerulus.
Macrophage impairment As mentioned earlier, APOE mutations have a principal role in the pathogenesis of LPG. However, recent studies [8, 9] have suggested that other genetic or epigenetic factors are involved in the pathogenesis of LPG because of the low penetrance based on many asymptomatic carriers of APOE variants. Moreover, an animal model by virusmediated transduction of APOE-Sendai [13] also showed the low penetrance in an additional experiment [14]. Kanamaru et al. [15] reported that an Fcc receptor (FcRc) deficiency associated with graft-versus-host disease caused murine LPG independently of the apoE abnormality. Our experiment [16] also clarified that the formation of lipoprotein thrombi in this murine model was induced by the impairment of macrophages, in which FcRc deficiency suppressed the activity of LDL and scavenger receptors. Moreover, Ito et al. [17] generated LPG-like changes in apoE and FcRc double knockout mice by injecting various apoE vectors that were associated with impaired macrophage function.
Interestingly, the role of FcRc was clinically recognized by the therapeutic effect of immunoadsorption on LPG using protein A columns [18]. Because protein A has strong affinity to the Fc portion of immunoglobulin G (IgG) and acts as FcRc, protein A may be able to improve LPG by absorbing the accumulated lipoproteins in LPG, although its binding ability to lipoproteins remains unknown. These experimental and clinical results indicate that the macrophage impairment related to FcRc dysfunction is among the pivotal factors of LPG development. In renal lipidosis, the mechanism of atherosclerosis proposed by Brown and Goldstein [19] may generally apply to the cause of glomerulosclerosis [20]. The increase of LDLcholesterol facilitates uptake of lipoproteins into mesangial cells or macrophages infiltrating the mesangial areas and contributes to the development of glomerulosclerosis with foam cells. In contrast, the macrophage impairment in LPG, as described earlier may provide a different mechanism of renal lipidosis in which massive lipoproteins accumulate in the extracellular area and develop into lipoprotein thrombi without a foamy change of the macrophage (Fig. 1).
Hypertriglyceridemia and therapeutic effect LPG is usually associated with type III hyperlipoproteinemia in which triglyceride (TG)-rich lipoproteins, such as very low density lipoproteins (VLDL) and intermediate
123
Clin Exp Nephrol
density lipoproteins (IDL) are the major components [4], and severe hypertriglyceridemia aggravates the features of LPG in both human cases [21] and animal models [13, 17]. From this point of view, preventing hypertriglyceridemia may be an important point in LPG treatment. Recently, the efficacy of lipid-lowering therapy containing fibrates has been reported by several authors from Japan, both clinically and histologically. In addition, Hu et al. [9] reviewed these case reports in detail and compared the 3-year patient and renal survival rates between their own fenofibratetreated and control groups. As a result, the significantly higher survival rate in the fenofibrate group confirmed the availability of fibrates. These therapeutic effects suggest that LPG can be ameliorated by the elimination of TG-rich lipoproteins composed of abnormal apoE. In the late stage of chronic kidney disease (CKD), levels of atherogenic TG-rich lipoproteins, including VLDL and IDL are increased. Regardless of the etiology, the abnormal lipid profile of LPG is similar to that of CKD. Therefore, the treatment of LPG may provide information about preventing CKD aggravation, although the side effects of lipid-lowering agents such as fibrates should be considered.
Conclusion Here, we introduced four LPG topics. Recent research results have helped with the elucidation of the pathogenesis of LPG and the development of its treatment. We hope that further studies in this field will help identify solutions of various problems in LPG and other lipid-induced nephropathies. Acknowledgments The studies described in this article were supported in part by grants-in-aid (nos. 10670982, 14571043, 16590806, 18590917, and 21591049) from the Ministry of Education, Science, Technology, Sports and Culture of Japan, and a Progressive Renal Diseases Research Projects grant from the Ministry of Health, Labour and Welfare of Japan. Conflict of interest interest exists.
The authors have declared that no conflict of
References 1. Saito T, Sato H, Kudo K, Oikawa S, Shibata T, Hara Y, et al. Lipoprotein glomerulopathy: glomerular lipoprotein thrombi in a patient with hyperlipoproteinemia. Am J Kidney Dis. 1989;13: 148–53. 2. Watanabe Y, Ozaki I, Yoshida F, Fukatsu A, Itoh Y, Matsuo S, et al. A case of nephrotic syndrome with glomerular lipoprotein deposition with capillary ballooning and mesangiolysis. Nephron. 1989;51:265–70. 3. Saito T, Matsunaga A, Oikawa S. Impact of lipoprotein glomerulopathy on the relationship between lipids and renal diseases. Am J Kidney Dis. 2006;47:199–211.
123
4. Oikawa S, Suzuki N, Sakuma E, Saito T, Namai K, Kotake H, et al. Abnormal lipoprotein and apolipoprotein pattern in lipoprotein glomerulopathy. Am J Kidney Dis. 1991;18:553–8. 5. Oikawa S, Matsunaga A, Saito T, Sato H, Seki T, Hoshi K, et al. Apolipoprotein E Sendai (arginine145 ? proline): a new variant associated with lipoprotein glomerulopathy. J Am Soc Nephrol. 1997;8:820–3. 6. Matsunaga A, Sasaki J, Komatsu T, Kanatsu K, Tsuji E, Moriyama K, et al. A novel apolipoprotein E mutation, E2 (Arg25Cys), in lipoprotein glomerulopathy. Kidney Int. 1999;56:421–7. 7. Saito T, Matsunaga A. Lipoprotein glomerulopathy may provide a key to unlock the puzzles of renal lipidosis. Kidney Int 2013 (in press). 8. Toyota K, Hashimoto T, Ogino D, Matsunaga A, Ito M, Masakane I, et al. A founder haplotype of APOE-Sendai mutation associated with lipoprotein glomerulopathy. J Hum Genet. 2013;58:254–8. 9. Hu Z, Huang S, Wu Y, Liu Y, Liu X, Su D, et al. Hereditary features, treatment, and prognosis of the lipoprotein glomerulopathy in patients with the APOE Kyoto mutation. Kidney Int 2013 [Epub ahead of print]. 10. Hoffmann M, Scharnagl H, Panagiotou E, Banghard W, Wieland H, Ma¨rz W. Diminished LDL receptor and high heparin binding of apolipoprotein E2 Sendai associated with lipoprotein glomerulopathy. J Am Soc Nephrol. 2001;12:524–30. 11. Georgiadou D, Stamatakis K, Efthimiadou EK, Kordas G, Gantz D, Chroni A, et al. Thermodynamic and structural destabilization of apoE3 by hereditary mutations associated with the development of lipoprotein glomerulopathy. J Lipid Res. 2013;54:164–76. 12. Russi G, Furci L, Leonelli M, Magistroni R, Romano N, Rivasi P, et al. Lipoprotein glomerulopathy treated with LDL-apheresis (heparin-induced extracorporeal lipoprotein precipitation system): a case report. J Med Case Rep. 2009;3:9311. 13. Ishigaki Y, Oikawa S, Suzuki T, Usui S, Magoori K, Kim DH, et al. Virus-mediated transduction of apolipoprotein E (ApoE)Sendai develops lipoprotein glomerulopathy in ApoE-deficient mice. J Biol Chem. 2000;275:31269–73. 14. Ishimura A, Watanabe M, Nakashima H, Ito K, Miyake K, Mochizuki S, et al. Lipoprotein glomerulopathy induced by ApoE-Sendai is different from glomerular lesions in aged apoEdeficient mice. Clin Exp Nephrol. 2009;13:430–7. 15. Kanamaru Y, Nakao A, Shirato I, Okumura K, Ogawa H, Tomino Y, et al. Chronic graft-versus-host autoimmune disease in Fc receptor gamma chain-deficient mice results in lipoprotein glomerulopathy. J Am Soc Nephrol. 2002;13:1527–33. 16. Miyahara Y, Nishimura S, Watanabe M, Ito K, Nakashima H, Saito T. Scavenger receptor expressions in the kidneys of mice with lipoprotein glomerulopathy. Clin Exp Nephrol. 2012;16: 115–21. 17. Ito K, Nakashima H, Watanabe M, Ishimura A, Miyahara Y, Abe Y, et al. Macrophage impairment produced by Fc receptor gamma deficiency plays a principal role in the development of lipoprotein glomerulopathy in concert with apoE abnormalities. Nephrol Dial Transplant. 2012;27:3899–907. 18. Xin Z, Zhihong L, Shijun L, Jinfeng Z, Huiping C, Caihong Z, et al. Successful treatment of patients with lipoprotein glomerulopathy by protein A immunoadsorption: a pilot study. Nephrol Dial Transplant. 2009;24:864–9. 19. Brown MS, Goldstein JL. Lipoprotein metabolism in the macrophage: implications for cholesterol deposition in atherosclerosis. Annu Rev Biochem. 1983;52:223–61. 20. Ricardo SD, van Goor H, Diamond JR. Hypercholesterolemia and progressive kidney disease: the role of macrophages and macrophage-derived products. Contrib Nephrol. 1997;120:197–209. 21. Saito T, Oikawa S, Sato H, Sasaki J. Lipoprotein glomerulopathy: renal lipidosis induced by novel apolipoprotein E variants. Nephron. 1999;83:193–201.
REVIEW ARTICLE
WCN 2013 Satellite Symposium ‘‘Kidney and Lipids’’
Topics in lipoprotein glomerulopathy: an overview Takao Saito • Akira Matsunaga • Kenji Ito Hitoshi Nakashima
•
Received: 29 September 2013 / Accepted: 3 October 2013 Ó Japanese Society of Nephrology 2013
Abstract Here, we introduce four topics in lipoprotein glomerulopathy (LPG). To date, approximately 150 cases of LPG have been reported worldwide. Recently two groups studied hot spots of APOE-Sendai and APOEKyoto, the representative variants of LPG, in narrow areas of Japan and China, respectively. They suggest that both variants have descended through a founder effect. APOESendai and APOE-Kyoto cause different transformations of apolipoproteins aggregating lipoproteins and resulting in lipoprotein thrombi within the glomerulus. Moreover, the macrophage impairment in LPG may provide another mechanism for lipoprotein thrombi in which massive lipoproteins accumulate in the glomerulus without foam cells. On the other hand, the administration of fibrate with the intensive control of triglyceride and apolipoprotein E particularly from the early phase will ameliorate LPG and prevent renal dysfunction. Keywords Founder effect ApoE transformation Macrophage impairment Fibrate
T. Saito (&) General Medical Research Center, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan e-mail: [email protected] A. Matsunaga Department of Laboratory Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan K. Ito H. Nakashima Division of Nephrology and Rheumatology, Department of Internal Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
Introduction The concept of lipoprotein glomerulopathy (LPG) was first discussed in the Annual Meeting of the Japanese Society of Nephrology in 1988 on the basis of five cases, and published in 1989 by both our group [1] and Watanabe et al. [2]. At the time of discovery, extremely dilated glomerular capillaries filled with huge lipoprotein-rich materials called lipoprotein thrombi were histologically characteristic. Clinically, proteinuria was sometimes mild but progressed to nephrotic syndrome in most cases [3]. Dyslipidemia generally classified into type III hyperlipoproteinemia was marked and associated with high serum apolipoprotein E (apoE) levels [4], although no systemic manifestations related to lipidosis, such as corneal opacity, xanthoma striata palmaris or other xanthomas, were observed. Moreover, the familial occurrence of LPG has been frequently recognized, and heterozygous novel APOE variants, that is, APOE-Sendai and APOE-Kyoto, were identified in the cases of LPG by Oikawa et al. [5] and Matsunaga et al. [6] in 1997 and 1998, respectively. Therefore, we believe that LPG is an inherited disease in which abnormal lipoproteins composed of apoE mutants accumulate within the glomerulus. However, asymptomatic carriers with such mutants have demonstrated the low genetic penetrance and suggested other etiological factors concerned with LPG. Recent clinical and experimental studies have produced valuable results and elucidated the pathogenic mechanisms and useful treatments. We discuss topics related to these matters here.
Distribution of LPG cases and the founder effect To date, approximately 150 cases of LPG have been reported worldwide. These cases were mainly in East Asia,
123
Clin Exp Nephrol Table 1 Analyzed DNA sequences of lipoprotein glomerulopathy by country APOE mutation
Japan
APOE-Sendai
25
APOE-Kyoto
6
APOE-Tokyo/Maebashi
2
APOE-Guanzhou APOE-Chicago APOE-Osaka/Kurashikio
China
Hong Kong
Taiwan
USA
France
Italy
Total
0
0
0
0
0
0
25
39
0
1
2
1
0
49
5
0
0
0
0
0
7
0
4
0
0
0
0
0
4
2
0
0
0
1
0
0
3
2
0
0
0
0
0
0
2
APOE2 (Classic)
2
0
0
0
0
0
0
2
Other APOE mutations*
5
0
1
0
1
0
1
8
No APOE Mutation
0
17
0
0
0
0
0
17
44
65
1
1
4
1
1
117
Total
* APOE-Tsukuba, APOE-Okayama, APOE-Kanto, APOE1(del 156–173), APOE5(Glu3Lys), APOE-Hong Kong, APOE-Las Vegas and APOEModena (one case each)
including Japan and China, but several were also seen in Europe and the United States [3]. After the discoveries of apoE-Sendai (Arg145Cys) in 1997 [5] and apoE-Kyoto (Arg25Cys) in 1998 [6], which are specific for LPG, DNA sequence analysis of the APOE gene has been recognized as the most important tool for identifying the diagnostic criteria of LPG [3]. To our knowledge, this testing was conducted in 117 cases of LPG [7] (Table 1). The polymorphism of the APOE mutation in LPG is clearly established since the identification of 15 novel APOE variants. However, the histological findings and clinical manifestations seem to be common among patients with different APOE variants. ApoE-Sendai, a major variant, was limited in patients who lived in east Japan, particularly in a narrow area lying across Yamagata and Miyagi prefectures. From this point of view, Toyota et al. [8] investigated the haplotype of APOE-Sendai in 13 Japanese patients with LPG from nine unrelated families and suggested that the APOE-Sendai mutation is common in Japanese patients through a founder effect. In contrast, APOE-Kyoto, the other major variant, has been distributed throughout the world. Namely, this mutation was found in not only among Asians in Japan, China and Taiwan but also among Caucasians in Europe and the United States [7]. Recently, Hu et al. [9] detected a hot spot of LPG with APOE-Kyoto in a narrow area of the Sichuan Basin, China, and investigated the genetic and clinical features of 35 patients with LPG and 28 asymptomatic carriers in 31 families. Their in depth and detailed study findings also suggest that the descent of APOE-Kyoto in this area was derived from a single founder. Accordingly, it is of interest that the incidence of APOE-Sendai and APOE-Kyoto, the major LPG mutants, may both have increased through a founder effect. However, the connection of APOE-Kyoto between Sichuan Basin and other areas cannot be easily explained unless the haplotypes of
123
APOE-Kyoto are compared worldwide. Of course, it may be possible that APOE-Kyoto spread worldwide from China because it is historically known that the international exchange of Chinese people has been popular from ancient times compared to that of Japanese people who are surrounded by the sea. This theory may be similar to the fact that tea culture expanded worldwide from China. Several other APOE variants have recently been reported in Europe and the United States as well as in Asia. Other hot spots of APOE variants associated with LPG may be detected across the world.
ApoE structure and glomerular injury Apart from the influence of type III hyperlipoproteinemia that is usually found in LPG, the apoE structural deformities that result from APOE mutations may play a pivotal role in the development of lipoprotein thrombi in the glomerulus. In particular, substitutions of proline for arginine in apoESendai, apoE-Chicago, apoE-Guangzhou and apoE-Osaka/ Kurashiki loosen the a-helix structure and transform the low-density lipoprotein (LDL)-receptor binding site in apoE. In this point of view, Hoffmann et al. [10] suggested that apoE-Sendai revealed reduction of receptor binding activity. Recently, Georgiadou et al. [11] have discovered in their detailed biochemical analysis that these mutations induce significant folding defects that extend to the whole N-terminal domain of the protein. They also mentioned that these findings provide novel mechanistic insight for the role of these mutants in the pathogenesis of LPG. Meanwhile, in apoE-Kyoto, a mutant point differs from an LDL-receptor binding domain and may not be involved in the binding defect of the LDL receptor. However, in an in vitro competition assay using apoE lysosomes, Matsunaga et al. [6] showed that apoE-Kyoto has only 10 % of the normal receptor-binding activity. Moreover, it is
Clin Exp Nephrol
Fig. 1 Comparison of the pathogenesis of lipoprotein glomerulopathy and hypercholesterolemic glomerulosclerosis (hypothetic)
possible that the residue of cysteine 25 is exposed on the surface of apoE and form a disulphide bridge with the other cysteine residue resulting in the large aggregation of apoE [12]. These findings also suggest the mechanism of lipoprotein thrombi in the glomerulus.
Macrophage impairment As mentioned earlier, APOE mutations have a principal role in the pathogenesis of LPG. However, recent studies [8, 9] have suggested that other genetic or epigenetic factors are involved in the pathogenesis of LPG because of the low penetrance based on many asymptomatic carriers of APOE variants. Moreover, an animal model by virusmediated transduction of APOE-Sendai [13] also showed the low penetrance in an additional experiment [14]. Kanamaru et al. [15] reported that an Fcc receptor (FcRc) deficiency associated with graft-versus-host disease caused murine LPG independently of the apoE abnormality. Our experiment [16] also clarified that the formation of lipoprotein thrombi in this murine model was induced by the impairment of macrophages, in which FcRc deficiency suppressed the activity of LDL and scavenger receptors. Moreover, Ito et al. [17] generated LPG-like changes in apoE and FcRc double knockout mice by injecting various apoE vectors that were associated with impaired macrophage function.
Interestingly, the role of FcRc was clinically recognized by the therapeutic effect of immunoadsorption on LPG using protein A columns [18]. Because protein A has strong affinity to the Fc portion of immunoglobulin G (IgG) and acts as FcRc, protein A may be able to improve LPG by absorbing the accumulated lipoproteins in LPG, although its binding ability to lipoproteins remains unknown. These experimental and clinical results indicate that the macrophage impairment related to FcRc dysfunction is among the pivotal factors of LPG development. In renal lipidosis, the mechanism of atherosclerosis proposed by Brown and Goldstein [19] may generally apply to the cause of glomerulosclerosis [20]. The increase of LDLcholesterol facilitates uptake of lipoproteins into mesangial cells or macrophages infiltrating the mesangial areas and contributes to the development of glomerulosclerosis with foam cells. In contrast, the macrophage impairment in LPG, as described earlier may provide a different mechanism of renal lipidosis in which massive lipoproteins accumulate in the extracellular area and develop into lipoprotein thrombi without a foamy change of the macrophage (Fig. 1).
Hypertriglyceridemia and therapeutic effect LPG is usually associated with type III hyperlipoproteinemia in which triglyceride (TG)-rich lipoproteins, such as very low density lipoproteins (VLDL) and intermediate
123
Clin Exp Nephrol
density lipoproteins (IDL) are the major components [4], and severe hypertriglyceridemia aggravates the features of LPG in both human cases [21] and animal models [13, 17]. From this point of view, preventing hypertriglyceridemia may be an important point in LPG treatment. Recently, the efficacy of lipid-lowering therapy containing fibrates has been reported by several authors from Japan, both clinically and histologically. In addition, Hu et al. [9] reviewed these case reports in detail and compared the 3-year patient and renal survival rates between their own fenofibratetreated and control groups. As a result, the significantly higher survival rate in the fenofibrate group confirmed the availability of fibrates. These therapeutic effects suggest that LPG can be ameliorated by the elimination of TG-rich lipoproteins composed of abnormal apoE. In the late stage of chronic kidney disease (CKD), levels of atherogenic TG-rich lipoproteins, including VLDL and IDL are increased. Regardless of the etiology, the abnormal lipid profile of LPG is similar to that of CKD. Therefore, the treatment of LPG may provide information about preventing CKD aggravation, although the side effects of lipid-lowering agents such as fibrates should be considered.
Conclusion Here, we introduced four LPG topics. Recent research results have helped with the elucidation of the pathogenesis of LPG and the development of its treatment. We hope that further studies in this field will help identify solutions of various problems in LPG and other lipid-induced nephropathies. Acknowledgments The studies described in this article were supported in part by grants-in-aid (nos. 10670982, 14571043, 16590806, 18590917, and 21591049) from the Ministry of Education, Science, Technology, Sports and Culture of Japan, and a Progressive Renal Diseases Research Projects grant from the Ministry of Health, Labour and Welfare of Japan. Conflict of interest interest exists.
The authors have declared that no conflict of
References 1. Saito T, Sato H, Kudo K, Oikawa S, Shibata T, Hara Y, et al. Lipoprotein glomerulopathy: glomerular lipoprotein thrombi in a patient with hyperlipoproteinemia. Am J Kidney Dis. 1989;13: 148–53. 2. Watanabe Y, Ozaki I, Yoshida F, Fukatsu A, Itoh Y, Matsuo S, et al. A case of nephrotic syndrome with glomerular lipoprotein deposition with capillary ballooning and mesangiolysis. Nephron. 1989;51:265–70. 3. Saito T, Matsunaga A, Oikawa S. Impact of lipoprotein glomerulopathy on the relationship between lipids and renal diseases. Am J Kidney Dis. 2006;47:199–211.
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