Skip to main content
SpringerLink
Log in

Lipoprotein glomerulopathy induced by ApoE-Sendai is different from glomerular lesions in aged apoE-deficient mice

  • Original Article
  • Published:
Clinical and Experimental Nephrology Aims and scope Submit manuscript

Abstract

Objective

A mutant of apolipoproteinE (apoE), ApoE-Sendai (Arg145Pro), is one of the major causative factors of human lipoprotein glomerulopathy (LPG). An apoE-deficient mouse with introduced ApoE-Sendai gene (ApoE-Sendai mouse) developed a murine counterpart of LPG, whereas it was also reported that apoE-deficient mouse (apoE KO mouse) spontaneously developed LPG-like lesion regardless of introduction of ApoE-Sendai gene. In the present study, we differentiated renal lesions between these two models by detailed analyses of histology and lipoprotein profile, and clarified the role of apoE variants.

Method

ApoE-Sendai mice were induced by injection of adenovirus vectors. The kidneys showing LPG-like lesions in apoE-Sendai and apoE KO mice were histopathologically evaluated. Plasma lipids and lipoproteins of both mice were also examined.

Results

Histological alteration of the kidney in ApoE-Sendai mice was observed with light microscopy (in 40 out of 50 mice; mild 24, moderate 13, severe 3). Characteristic lesions were dilated vascular lumens mimicking lipoprotein thrombi in human LPG. Similar changes were found in hematoxylin–eosin stained sections of aged apoE KO mice. Meanwhile, periodic acid–Schiff, Azan Mallory, and Oil red O/Sudan III stained sections revealed that the dilated lumens of ApoE-Sendai mice mainly contained lipids and lipoproteins but those of aged apoE KO mice contained much other materials, e.g., proteins and fibrils. These findings were supported by electron micrographs, in which round-shaped droplets indicating lipoproteins were observed in ApoE-Sendai mice but not in aged apoE KO mice. In the kidney of apoE KO mice many anti-mouse CD68 Ab positive cells were detected. This contrasts with the result seen in ApoE-Sendai mice. The plasma lipoprotein compositions of the two types of mice were totally different.

Conclusion

It was certain that the kidneys of aged apoE KO mice showed morphological alteration, but the histological findings of glomerular lesions were different from those seen in the kidneys of ApoE-Sendai mice. According to the histological findings and plasma lipoprotein profile, ApoE-Sendai mice, not apoE KO mice, is a murine model for human LPG. This means that apoE variants are essential to LPG.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

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.

    Article  CAS  PubMed  Google Scholar 

  2. Saito T, Oikawa S, Sato H, Sasaki J. Lipoprotein glomerulopathy: renal lipidosis induced by novel apolipoprotein e variants. Nephron. 1999;83:193–201.

    Article  CAS  PubMed  Google Scholar 

  3. 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.

    Article  CAS  PubMed  Google Scholar 

  4. Oikawa S, Matsunaga A, Saito T, Sato H, Seki T, Hoshi K, et al. Apolipoprotein e sendai (arginine 145–proline): a new variant associated with lipoprotein glomerulopathy. J Am Soc Nephrol. 1997;8:820–3.

    CAS  PubMed  Google Scholar 

  5. Konishi K, Saruta T, Kuramochi S, Oikawa S, Saito T, Han H, et al. Association of a novel 3-amino acid deletion mutation of apolipoprotein e (apo e tokyo) with lipoprotein glomerulopathy. Nephron. 1999;83:214–8.

    Article  CAS  PubMed  Google Scholar 

  6. Ando M, Sasaki J, Hua H, Matsunaga A, Uchida K, Jou K, et al. A novel 18-amino acid deletion in apolipoprotein e associated with lipoprotein glomerulopathy. Kidney Int. 1999;56:1317–23.

    Article  CAS  PubMed  Google Scholar 

  7. 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.

    Article  CAS  PubMed  Google Scholar 

  8. Ogawa T, Maruyama K, Hattori H, Arai H, Kondoh I, Egashira T, et al. A new variant of apolipoprotein e (apo e maebashi) in lipoprotein glomerulopathy. Pediatr Nephrol. 2000;14:149–51.

    Article  CAS  PubMed  Google Scholar 

  9. Miyata T, Sugiyama S, Nangaku M, Suzuki D, Uragami K, Inagi R, et al. Apolipoprotein e2/e5 variants in lipoprotein glomerulopathy recurred in transplanted kidney. J Am Soc Nephrol. 1999;10:1590–5.

    CAS  PubMed  Google Scholar 

  10. Saito T, Ishigaki Y, Oikawa S, Yamamoto TT. Role of apolipoprotein e variants in lipoprotein glomerulopathy and other renal lipidoses. Clin Exp Nephrol. 2001;5:201–8.

    Article  CAS  Google Scholar 

  11. Lalazar A, Weisgraber KH, Rall SC Jr, Giladi H, Innerarity TL, Levanon AZ, et al. Site-specific mutagenesis of human apolipoprotein e. Receptor binding activity of variants with single amino acid substitutions. J Biol Chem. 1988;263:3542–5.

    CAS  PubMed  Google Scholar 

  12. de Knijff P, van den Maagdenberg AM, Frants RR, Havekes LM. Genetic heterogeneity of apolipoprotein e and its influence on plasma lipid and lipoprotein levels. Hum Mutat. 1994;4:178–94.

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    Article  CAS  PubMed  Google Scholar 

  14. Saito T, Sato H, Oikawa S, Kudo K, Kurihara I, Nakayama K, et al. Lipoprotein glomerulopathy. Report of a normolipidemic case and review of the literature. Am J Nephrol. 1993;13:64–8.

    Article  CAS  PubMed  Google Scholar 

  15. Saito T, Sato H, Oikawa S. Lipoprotein glomerulopathy: a new aspect of lipid induced glomerular injury. Nephrology. 1995;1:17–24.

    Article  Google Scholar 

  16. Saito T. Abnormal lipid metabolism and renal disorders. Tohoku J Exp Med. 1997;181:321–37.

    Article  CAS  PubMed  Google Scholar 

  17. Saito T, Ishigaki Y, Oikawa S, Yamamoto T. Etiological significance of novel apolipoprotein e variants in lipoprotein glomerulopathy. Trend Cardiovasc Med. 2002;12:67–70.

    Article  CAS  Google Scholar 

  18. Saito T, Oikawa S, Sato H, Sato T, Ito S, Sasaki J. Lipoprotein glomerulopathy: significance of lipoprotein and ultrastructural features. Kidney Int Suppl. 1999;71:S37–41.

    Article  CAS  PubMed  Google Scholar 

  19. Mochizuki S, Moriya T, Naganuma H, Sasano H, Saito T. Significance of fat stains in serial sections from epon-embedded tissue samples for electron microscopy in renal diseases. Clin Exp Nephrol. 2001;5:240–5.

    Article  Google Scholar 

  20. Churg J, Berstein J, Glassock RJ, editors. Lipoprotein glomerulopahy. In: Renal disease: classification and atlas of glomerular disease, 2nd ed. New York-Tokyo: Igaku-Shoin; 1995. p. 450–1.

  21. Finn LS, Berstein J. Lipoprotein glomerulopathy. In: Jennette JC, Olson JL, Schwartz MM, Silva FG, editors. Heptinstall’s pathology of the kidney. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2007. p. 1203–5.

  22. Appel GB, Radhakrishnan J, D’Agati V. Lipoprotein glomerulopathy. In: Brenner BM, editor. Brenner & Rector’s the kidney. 8th ed. Philadelphia: Saunders; 2008. p. 1118.

    Google Scholar 

  23. Fogo AB, Kashgarian M, editors. Lipoprotein glomerulopathy. In: Diagnostic atlas of renal pathology. 1st ed. Philadelpha: Elsevier Saunders; 2005. p. 168–71.

  24. 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.

    Article  CAS  PubMed  Google Scholar 

  25. Wen M, Segerer S, Dantas M, Brown PA, Hudkins KL, Goodpaster T, et al. Renal injury in apolipoprotein e-deficient mice. Lab Invest. 2002;82:999–1006.

    Article  CAS  PubMed  Google Scholar 

  26. Zhang SH, Reddick RL, Piedrahita JA, Maeda N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein e. Science. 1992;258:468–71.

    Article  CAS  PubMed  Google Scholar 

  27. Okazaki M, Usui S, Hosaki S. Analysis of plasma lipoproteins by gel permeation chromatography. In: Rifai N, Warmick GR, Dominiczak MH, editors. Handbook of lipoprotein testing. Washington, DC: AACC Press; 2000. p. 647–69.

    Google Scholar 

  28. Usui S, Nakamura M, Jitsukata K, Nara M, Hosaki S, Okazaki M. Assessment of between-instrument variations in a hplc method for serum lipoproteins and its traceability to reference methods for total cholesterol and hdl-cholesterol. Clin Chem. 2000;46:63–72.

    CAS  PubMed  Google Scholar 

  29. Vlassara H, Bucala R, Striker L. Pathogenic effects of advanced glycosylation: biochemical, biologic, and clinical implications for diabetes and aging. Lab Invest. 1994;70:138–51.

    CAS  PubMed  Google Scholar 

  30. Baylis C. Age-dependent glomerular damage in the rat. Dissociation between glomerular injury and both glomerular hypertension and hypertrophy. Male gender as a primary risk factor. J Clin Invest. 1994;94:1823–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Anderson S, Brenner BM. Effects of aging on the renal glomerulus. Am J Med. 1986;80:435–42.

    Article  CAS  PubMed  Google Scholar 

  32. Zheng F, Cheng QL, Plati AR, Ye SQ, Berho M, Banerjee A, et al. The glomerulosclerosis of aging in females: contribution of the proinflammatory mesangial cell phenotype to macrophage infiltration. Am J Pathol. 2004;165:1789–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Diamond JR, Karnovsky MJ. Focal and segmental glomerulosclerosis: analogies to atherosclerosis. Kidney Int. 1988;33:917–24.

    Article  CAS  PubMed  Google Scholar 

  34. Fazio S, Linton MF. Mouse models of hyperlipidemia and atherosclerosis. Front Biosci. 2001;6:D515–25.

    Article  CAS  PubMed  Google Scholar 

  35. Liberopoulos E, Siamopoulos K, Elisaf M. Apolipoprotein e and renal disease. Am J Kidney Dis. 2004;43:223–33.

    Article  CAS  PubMed  Google Scholar 

  36. 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.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study is supported in part by Grants-in-Aid (#16590806 and #18590917) from the Ministry of Education, Culture, Sports, Science, and Technology, and a grant for the Progressive Renal Disease Research Projects from the Ministry of Health, Labor, and Welfare, Japan.

Author information

Authors and Affiliations

  1. Division of Nephrology and Rheumatology, Department of Internal Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonann-ku, Fukuoka, 814-0180, Japan

    Atsunori Ishimura, Maho Watanabe, Hitoshi Nakashima, Kenji Ito, Katsuhisa Miyake & Takao Saito

  2. Department of Pathology, Tohoku University Hospital, Sendai, Japan

    Shizue Mochizuki

  3. Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan

    Yasushi Ishigaki

Authors
  1. Atsunori Ishimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maho Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hitoshi Nakashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kenji Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Katsuhisa Miyake
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shizue Mochizuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yasushi Ishigaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Takao Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hitoshi Nakashima.

About this article

Cite this article

Ishimura, A., Watanabe, M., Nakashima, H. et al. Lipoprotein glomerulopathy induced by ApoE-Sendai is different from glomerular lesions in aged apoE-deficient mice. Clin Exp Nephrol 13, 430–437 (2009). https://doi.org/10.1007/s10157-009-0195-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10157-009-0195-1

Keywords

Search

Navigation