Skip to main content
SpringerLink
Log in

Immunohistochemical localization of advanced glycation end-products (AGEs) and their receptor (RAGE) in polycystic and normal ovaries

  • Original Paper
  • Published:
Histochemistry and Cell Biology Aims and scope Submit manuscript

Abstract

The aim of the present study was to investigate the localization/immunohistochemical distribution of AGEs and RAGE, as well as their putative signalling mediator NF-κB in ovaries of women with polycystic ovary syndrome (PCOS) compared to normal. Archival ovarian-tissue samples from biopsies of six women with PCOS and from six healthy of similar age women, were examined immunohistochemically with monoclonal anti-AGEs, anti-RAGE and anti-NF-κB(p50/p65) specific antibodies. In healthy women, AGE immunoreactivity was observed in follicular cell layers (granulosa and theca) and luteinized cells, but not in endothelial cells. PCOS specimens displayed AGE immunoexpression in theca interna and granulosa cells as well as in endothelial cells, but staining of granulosa cells was stronger than in that of normal ovaries. RAGE was highly expressed in normal and PCOS tissues. Normal tissue exhibited no staining differences between granulosa cell layer and theca interna. However, in PCOS ovaries, granulosa cells displayed stronger RAGE expression compared to theca interna cells in comparison to controls. NF-κB(p50/p65) was expressed in the cytoplasm of theca interna and granulosa cells of both normal and PCOS ovaries; whereas the NF-κB p65 subunit was only observed in granulosa cells nuclei in PCOS tissue. In conclusion, these findings demonstrate for the first time that RAGE and AGE-modified proteins with activated NF-κB are expressed in human ovarian tissue. Furthermore, a differential qualitative distribution of AGE, RAGE and NF-κB p65 subunit was observed in women with PCOS compared to healthy controls, where a stronger localization of both AGE and RAGE was observed in the granulosa cell layer of PCOS ovaries.

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

  • Abe H, Matsubara T, Iehara N, et al (2004) Type IV collagen is transcriptionally regulated by Smad1 under advanced glycation end product (AGE) stimulation. J Biol Chem 279:14201–14206

    Article  PubMed  CAS  Google Scholar 

  • Baldwin AS (1996) The NF-κB and IκB proteins: new discoveries and insights. Ann Rev Immunol 14:649–681

    Article  CAS  Google Scholar 

  • Bierhaus A, Illmer T, Kasper M, Luther T, Quehenberger P, Tritschler H, Wahl P, Ziegler R, Muller M, Nawroth PP (1997) Advanced glycation end product (AGE)-mediated induction of tissue factor in cultured endothelial cells is dependent on RAGE. Circulation 96:2262–2271

    PubMed  CAS  Google Scholar 

  • Cai W, He JC, Zhu L, et al (2004) High levels of dietary advanced glycation end products transform low-density lipoprotein into a potent redox sensitive mitogen-activated protein kinase stimulant in diabetic patients. Circulation 110:285–291

    Article  PubMed  CAS  Google Scholar 

  • Cerami C, Founds H, Nicholl I, et al (1997) Tobacco smoke is a source of toxic reactive glycation products. Proc Natl Acad Sci USA 94:13915–13920

    Article  PubMed  CAS  Google Scholar 

  • Conway GS, Agrawal R, Betteridge DJ, Jacobs HS (1992) Risk factors for coronary artery disease in lean and obese women with the polycystic ovary syndrome. Clin Endocrinol 37:119–125

    CAS  Google Scholar 

  • Dan Q, Wong RL, Yin S, Chung SK, Chung SS, Lam KS (2004) Interaction between the polyol pathway and non-enzymatic glycation on mesangial cell gene expression. Nephron Exp Nephrol 98:e89–e99

    Article  PubMed  CAS  Google Scholar 

  • Diamanti-Kandarakis E, Dunaif A (1996) New perspectives in polycystic ovary syndrome. Trends Endocrinol Metab 7:267–271

    Article  CAS  PubMed  Google Scholar 

  • Diamanti-Kandarakis E, Kouli CR, Bergiele AT, et al (1999) A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal and metabolic profile. J Clin Endocrinol Metab 84:4006–4011

    Article  PubMed  CAS  Google Scholar 

  • Diamanti-Kandarakis E, Spina G, Kouli C, Migdalis I (2001) Increased endothelin-1 levels in women with polycystic ovary syndrome and the beneficial effect of metformin therapy. J Clin Endocrinol Metab 86:4666–4673

    Article  PubMed  CAS  Google Scholar 

  • Diamanti-Kandarakis E, Palioniko G, Alexandraki K, Bergiele A, Koutsouba T, Bartzis M (2004) The prevalence of 4G5G polymorphism of plasminogen activator inhibitor-1 (PAI-1) gene in polycystic ovarian syndrome and its association with plasma PAI-1 levels. Eur J Endocrinol 150:793–798

    Article  PubMed  CAS  Google Scholar 

  • Diamanti-Kandarakis E, Alexandraki K, Protogerou A, Piperi C, Papamichael C, Aessopos A, Lekakis J, Mavrikakis M (2005a) Metformin administration improves endothelial function in women with polycystic ovary syndrome. Eur J Endocrinol 152:749–756

    Article  CAS  Google Scholar 

  • Diamanti-Kandarakis E, Piperi C, Creatsas G, Kalofoutis A (2005b) Increased levels of advanced glycation end products in women with polycystic ovary syndrome. Clin Endocrinol 62:37–43

    Article  CAS  Google Scholar 

  • Diamanti-Kandarakis E, Piperi C, Alexandraki K, et al (2006) Short-term effect of orlistat on dietary glycotoxins in healthy women and women with polycystic ovary syndrome. Metabolism 55:494–500

    Article  PubMed  CAS  Google Scholar 

  • Duleba AJ, Banaszewska B, Spaczynski RZ, Pawelczyk L (2003) Success of laparoscopic ovarian wedge resection is related to obesity, lipid profile, and insulin levels. Fertil Steril 79:1008–1014

    Article  PubMed  Google Scholar 

  • Dunaif A, Wu X, Lee A, Diamanti-Kandarakis E (2001) Defects in insulin receptor signaling in vivo in the polycystic ovary syndrome (PCOS). Am J Physiol Endocrinol Metab 281:E392–E399

    PubMed  CAS  Google Scholar 

  • Glueck CJ, Wang P, Fontaine RN, Sieve-Smith L, Tracy T, Moore SK (1999) Plasminogen activator inhibitor activity: an independent risk factor for the high miscarriage rate during pregnancy in women with polycystic ovary syndrome. Metabolism 48:1589–1595

    Article  PubMed  CAS  Google Scholar 

  • Harlow CR, Rae M, Davidson L, Trackman PC, Hillier SG (2003) Lysyl oxidase gene expression and enzyme activity in the rat ovary: regulation by follicle-stimulating hormone, androgen, and transforming growth factor-beta superfamily members in vitro. Endocrinology 144:154–162

    Article  PubMed  CAS  Google Scholar 

  • Henmi H, Endo T, Nagasawa K, et al (2001) Lysyl oxidase and MMP-2 expression in dehydroepiandrosterone-induced polycystic ovary in rats. Biol Reprod 64:157–162

    Article  PubMed  CAS  Google Scholar 

  • Hori O, Brett J, Slattery T, et al (1995) The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J Biol Chem 270:25752–25761

    Article  PubMed  CAS  Google Scholar 

  • Horiuchi S, Araki N, Morino Y (1991) Immunochemical approach to characterize advanced glycation end products of the Maillard reaction; evidence for the presence of a common structure. J Biol Chem 266:7329–7332

    PubMed  CAS  Google Scholar 

  • Ikeda K, Higashi T, Sano H, Jinnouchi Y, Yoshida M, Araki T, Ueda S, Horiuchi S (1996) Ne-(carboxymethyl) lysine protein adduct is a major immunological epitope in proteins modified withadvanced glycation end products of the Maillard reaction. Biochemistry 35:8075–8083

    Article  PubMed  CAS  Google Scholar 

  • Karin M, Ben Neriah Y (2000) Phosphorylation meets ubiquitination: the control of NF-kB activity. Annu Rev Immunol 18:621–663

    Article  PubMed  CAS  Google Scholar 

  • Kirstein M, Brett J, Radoff S, Ogawa S, Stern D, Vlassara H (1990) Advanced protein glycosylation induces transendothelial human monocyte chemotaxis and secretion of platelet-derived growth factor: role in vascular disease of diabetes and aging. Proc Natl Acad Sci USA 87:9010–9014

    Article  PubMed  CAS  Google Scholar 

  • Krueger A, Schmitz I, Baumann S, Krammer PH, Kirchhoff S (2001) Cellular FLICE-inhibitory protein splice variants inhibit different steps of caspase-8 activation at the CD95 death-inducing signaling complex. J Biol Chem 276:20633–20640

    Article  PubMed  CAS  Google Scholar 

  • Kruk PA, Uitto VJ, Firth JD, Dedhar S, Auersperg N (1994) Reciprocal interactions between human ovarian surface epithelial cells and adjacent extracellular matrix. Exp Cell Res 215:97–108

    Article  PubMed  CAS  Google Scholar 

  • Ligier S, Fortin PR, Newkirk MM (1998) A new antibody in rheumatoid arthritis targeting glycated IgG: IgM anti-IgG-AGE. Br J Rheumatol 37:1307–1314

    Article  PubMed  CAS  Google Scholar 

  • Liu YX (1999) Regulation of the plasminogen activator system in the ovary. Biol Signals Recept 8:160–177

    Article  PubMed  CAS  Google Scholar 

  • Loske C, Neumann A, Cunningham AM, Nichol K, Schinzel R, Riederer P, Munch G (1998) Cytotoxicity of advanced glycation endproducts is mediated by oxidative stress. J Neural Transm 105:1005–1015

    Article  PubMed  CAS  Google Scholar 

  • Loske C, Gerdemann A, Schepl W, et al (2000) Transition metal-mediated glycoxidation accelerates cross-linking of beta-amyloid peptide. Eur J Biochem 267:4171–4178

    Article  PubMed  CAS  Google Scholar 

  • Matsuse S, Ohga E, Teramoto S, Fukayama M, Nagai R, Horiuchi S, Ouchi Y (1998) Immunohistochemical localisation of advanced glycation end products in pulmonary fibrosis. J Clin Pathol 51:515–519

    Article  PubMed  CAS  Google Scholar 

  • Mohamed AK, Bierhaus A, Schiekofer S, Tritschler H, Ziegler R, Nawroth PP (1999) The role of oxidative stress and NF-kB activation in late diabetic complications. Biofactors 10:157–167

    PubMed  CAS  Google Scholar 

  • Mott JD, Khalifah RG, Nagase H, Shield CF 3rd, Hudson JK, Hudson BG (1997) Nonenzymatic glycation of type IV collagen and matrix metalloproteinase susceptibility. Kidney Int 52:1302–1312

    Article  PubMed  CAS  Google Scholar 

  • Nakayama M, Kawaguchi Y, Yamada K, Hasegawa T, Takazoe K, Katoh N, Hayakawa H, Osaka N, Yamamoto H, Ogawa A (1997) Immunohistochemical detection of advanced glycosylation end-products in the peritoneum and its possible pathophysiological role in CAPD. Kidney Int 51:182–186

    Article  PubMed  CAS  Google Scholar 

  • Neumann A, Schinzel R, Palm D, Riederer P, Munch G (1999) High molecular weight hyaluronic acid inhibits advanced glycation endproduct-induced NF-kappaB activation and cytokine expression. FEBS Lett 453:283–287

    Article  PubMed  CAS  Google Scholar 

  • Nicholl ID, Bucala R (1998) Advanced glycation endproducts and cigarette smoking. Cell Mol Biol (Noisy-le-grand) 44:1025–1033

    CAS  Google Scholar 

  • Oksjoki S, Rahkonen O, Haarala M, Vuorio E, Anttila L (2004) Differences in connective tissue gene expression between normally functioning, polycystic and post-menopausal ovaries. Mol Hum Reprod 10:7–14

    Article  PubMed  CAS  Google Scholar 

  • Pugliese G, Pricci F, Romeo G, et al (1997) Upregulation of mesangial growth factor and extracellular matrix synthesis by advanced glycation end products via a receptor-mediated mechanism. Diabetes 46:1881–1887

    Article  PubMed  CAS  Google Scholar 

  • Puistola U, Martikainen H, Ronnberg L (1986) Type IV collagenolytic activity in human preovulatory follicular fluid. Fertil Steril 45:578–580

    PubMed  CAS  Google Scholar 

  • Read MA, Brownell JE, Gladysheva TB (2000) Nedd8 modification of cul-1 activates SCF(_(TrCP))-dependent ubiquitination of IκB. Mol Cell Biol 20:2326–2333

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez-Garcia J, Requena JR, Rodriguez-Segade S (1998) Increased concentrations of serum pentosidine in rheumatoid arthritis. Clin Chem 44:250–255

    PubMed  CAS  Google Scholar 

  • Rice S, Christoforidis N, Gadd C, et al (2005) Impaired insulin-dependent glucose metabolism in granulosa-lutein cells from anovulatory women with polycystic ovaries. Hum Reprod 20:373–381

    Article  PubMed  CAS  Google Scholar 

  • Sakata N, Imanaga Y, Meng J, Tachikawa Y, Takebayashi S, Nagai R, Horiuchi S, Itabe H, Takano T (1998) Immunohistochemical localization of different epitopes of advanced glycation end products in human atherosclerotic lesions. Atherosclerosis 141:61–75

    Article  PubMed  CAS  Google Scholar 

  • Sano H, Higashi T, Matsumoto K, et al (1998) Insulin enhances macrophage scavenger receptor-mediated endocytic uptake of advanced glycation end products. J Bioll Chem 273:8630–8637

    Article  CAS  Google Scholar 

  • Schmidt AM, Yan S-D, Wautier JL, Stern DM (1999) Activation of receptor for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis. Circ Res 84:489–497

    PubMed  CAS  Google Scholar 

  • Schmidt AM, Yan S-D, Yan S-F, Stern DM (2000) The biology of the receptor for advanced glycation end products and its ligands. Biochim Biophys Acta 1498:99–111

    Article  PubMed  CAS  Google Scholar 

  • Siebenlist U, Franzoso G, Brown K (1994) Structure, regulation and function of NF-κB. Ann Rev Cell Biol 10:405–455

    PubMed  CAS  Google Scholar 

  • Singh R, Barden A, Mori T, Beilin L (2001) Advanced glycation endproducts: a review. Diabetologia 44:129–146

    Article  PubMed  CAS  Google Scholar 

  • Tamm I, Trepel M, Cardó-Vila M, et al (2003) Peptides targeting caspase inhibitors. J Biol Chem 278:14401–14405

    Article  PubMed  CAS  Google Scholar 

  • Tsuchida K, Makita Z, Yamagishi S, et al (1999) Suppression of transforming growth factor beta and vascular endothelial growth factor in diabetic nephropathy in rats by a novel advanced glycation end product inhibitor, OPB-9195. Diabetologia 42:579–588

    Article  PubMed  CAS  Google Scholar 

  • Tsuji H, Iehara N, Masegi T, et al (1998) Ribozyme targeting of receptor for advanced glycation end products in mouse mesangial cells. Biochem Biophys Res Commun 245:583–588

    Article  PubMed  CAS  Google Scholar 

  • Vlassara H, Brownlee M, Cerami A (1985) High-affinity-receptor-mediated uptake and degradation of glucose-modified proteins: a potential mechanism for the removal of senescent macromolecules. Proc Natl Acad Sci USA 82:5588–5592

    Article  PubMed  CAS  Google Scholar 

  • Wu XK, Zhou SY, Liu JX, et al (2003) Selective ovary resistance to insulin signaling in women with polycystic ovary syndrome. Fertil Steril 80:954–965

    Article  PubMed  Google Scholar 

  • Xiao CW, Ash K, Tsang BK (2001) Nuclear factor-kB-mediated X-linked inhibitor of apoptosis protein expression prevents rat granulosa cells from tumor necrosis factor α-induced apoptosis. Endocrinology 142:557–563

    Article  PubMed  CAS  Google Scholar 

  • Xiao CW, Asselin E, Tsang BK (2002) Nuclear factor kB-mediated induction of flice-like inhibitory protein prevents tumor necrosis factor α-induced apoptosis in rat granulosa cells. Biol Reprod 67:436–441

    Article  PubMed  CAS  Google Scholar 

  • Yamada S, Fujiwara H, Honda T, et al (1999) Human granulosa cells express integrin a2 and collagen type IV: possible involvement of collagen type IV in granulosa cell luteinization. Mol Hum Reprod 5:607–617

    Article  PubMed  CAS  Google Scholar 

  • Yoshida S, Yoshida S, Yamada K, Hamaguchi K, Nishimura M, Hatakeyama E, Tsuchida H, Sakamoto K, Kashiwabara H, Yokoyama T (1998) Immunohistochemical study of human advanced glycation end-products and growth factors in cardiac tissues of patients on maintenance dialysis and with kidney transplantation. Clin Nephrol 49:273–280

    PubMed  CAS  Google Scholar 

  • Yui S, Sasaki T, Araki N, Horiuchi S, Yamazaki M (1994) Induction of macrophage growth by advanced glycation end products of the Maillard reaction. J Immunol 152:1943–1949

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. First Department of Internal Medicine, Endocrine section, University of Athens Medical School, 75, M. Asias Str., 11527, Athens, Greece

    Evanthia Diamanti-Kandarakis

  2. Department of Biological Chemistry, University of Athens Medical School, 75, M. Asias Str., 11527, Athens, Greece

    Christina Piperi & Athanasios G. Papavassiliou

  3. Department of Pathology, University of Athens Medical School, 75, M. Asias Str., 11527, Athens, Greece

    Efstratios Patsouris & Penelope Korkolopoulou

  4. Division of Endocrinology and Human Reproduction, Second Department of Obstetrics and Gynaecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Dimitrios Panidis

  5. Division of Infertility and Reproductive Endocrinology, Department of Gynecology and Obstetrics, Karol Marcinkowski University of Medical Sciences, Poznan, Poland

    Leszek Pawelczyk

  6. Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT, USA

    Antoni J. Duleba

  7. 1A Zefyrou Str., Ekali, 17562, Athens, Greece

    Evanthia Diamanti-Kandarakis

Authors
  1. Evanthia Diamanti-Kandarakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christina Piperi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Efstratios Patsouris
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Penelope Korkolopoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dimitrios Panidis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Leszek Pawelczyk
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Athanasios G. Papavassiliou
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Antoni J. Duleba
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Evanthia Diamanti-Kandarakis or Athanasios G. Papavassiliou.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Diamanti-Kandarakis, E., Piperi, C., Patsouris, E. et al. Immunohistochemical localization of advanced glycation end-products (AGEs) and their receptor (RAGE) in polycystic and normal ovaries. Histochem Cell Biol 127, 581–589 (2007). https://doi.org/10.1007/s00418-006-0265-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00418-006-0265-3

Keywords

Search

Navigation