Skip to main content

Advertisement

SpringerLink
Log in

Protective effects of pioglitazone against immunoglobulin deposition on heart of streptozotocin-induced diabetic rats

  • Original Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Aim

Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists have immunomodulatory and anti-inflammatory effects. The study investigated the autoimmune injuries of diabetic cardiomyopathy (DCM) and tested the hypothesis that PPAR-γ agonists suppress disordered immune responses in diabetic heart, thereby preventing evolution of DCM.

Methods

STZ-induced diabetic rats were assigned to five groups: DM group, given no treatment; INS group, given insulin (4U kg−1 d−1); PIL group, given low dose pioglitazone (4 mg kg−1 d−1); PIL/INS group, given both low dose pioglitazone and insulin; PIH group, given high dose pioglitazone (20 mg kg−1 d−1). Normal rats (CON group) were also monitored as control. The pathologic abnormalities of hearts were observed. The immunoglobulin deposition was examined by immunohistochemistry and immunofluorescence.

Results

At 16 weeks, interstitial fibrosis was shown in diabetic heart which was accompanied by plenty of inflammatory cells infiltrated. Pioglitazone therapy could ameliorate the cardiac injuries. Shown by immunohistochemistry, the difference of integrated optical density (IOD) of immunoglobulin deposition among each group had statistic significance. No obvious immunoglobulins were deposited in the intercellular substance of heart in CON group (IgA 290.8 ± 88.1, IgG 960.4 ± 316.0 and IgM 341.3 ± 67.9). But the deposition of immunoglobulins increased significantly in DM group (IgA 7,047.5 ± 1,328.3, P < 0.05; IgG 28,945.9 ± 5,160.7, P < 0.05 and IgM 8,580.8 ± 1,336.8, P < 0.05). Administration of pioglitazone greatly reduced the increased deposition in a dose-dependent fashion. Moreover, the statistical significance was the same with immunofluorescence analysis as with immunohistochemical examination.

Conclusions

The data suggest that disordered immune responses play an important role in the pathogenesis of DCM. Pioglitazone showed protective effects by inhibiting the immunoglobulin deposition on diabetic myocardium.

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. Gao H, Qiu M (2005) More research work should be done on the pathogenesis of autoimmune injuries to the multiple organs in some T2 diabetes Mellitus. Natl Med J China 85:793–795

    CAS  Google Scholar 

  2. Qiu M, Meng C (2006) The role of complement activation in the pathogenesis of diabetic complications. Chin J Endocrinol Metab 22:303–305

    CAS  Google Scholar 

  3. Meng C, Gao H, Qiu M et al (2006) Immunological injury on the retina in streptozotocin-induced diabetic rats. Chin J Endocrinol Metab 22:588–589

    CAS  Google Scholar 

  4. Zhang X, Cui J, Qiu M et al (2008) The effects of cyclosporine A on immunoglobulins deposition in retina of streptozotocin-induced diabetic rats. Chin J Intern Med 47:125–128

    CAS  Google Scholar 

  5. Cui J, Zhang P, Qiu M et al (2010) Preventive effects of cyclosporine A on immunoglobulins deposition on heart of STZ-induced diabetic rats. Chin J Diabetes Mellitus 2:142–147

    Google Scholar 

  6. Cui J, Qiu M, Li D et al (2010) The protective effects of cyclosporine A on aortic immunological injuries in STZ-induced diabetic rats. Chin J Cardiol 38:440–444

    Google Scholar 

  7. Pershadsingh HA (2004) Peroxisome proliferator-activated receptor-gamma: therapeutic target for diseases beyond diabetes: quo vadis? Expert Opin Investig Drugs 13:215–228

    Article  PubMed  CAS  Google Scholar 

  8. Lena S, Samir NP, Kodjo A et al (2009) Rosiglitazone modulates innate immune responses to Plasmodium falciparum and improves outcome in experimental cerebral malaria. J Infect Dis 199:1536–1545

    Article  CAS  Google Scholar 

  9. Cuzzocrea S, Pisano B, Dugo L et al (2004) Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor-gamma, reduces acute inflammation. Eur J Pharmacol 483:79–93

    Article  PubMed  CAS  Google Scholar 

  10. Antonelli A, Ferrari SM, Frascerra S et al (2010) CXCL9 and CXCL11 chemokines modulation by peroxisome proliferator-activated receptor-alpha agonists secretion in Graves’ and normal thyrocytes. J Clin Endocrinol Metab 95:E413–E420

    Article  PubMed  CAS  Google Scholar 

  11. Klotz L, Schmidt M, Giese T et al (2005) Proinflammatory stimulation and pioglitazone treatment regulate peroxisome proliferator-activated receptor gamma levels in peripheral blood mononuclear cells from healthy controls and multiple sclerosis patients. J Immunol 175:4948–4955

    Article  PubMed  CAS  Google Scholar 

  12. Von Knethen A, Brune B (2002) Activation of peroxisome proliferator activated receptor γ by nitric oxide in monocytes/macrophages down-regulates p47phox and attenuates the respiratory burst. J Immunol 169:2619–2626

    Article  Google Scholar 

  13. Faine LA, Rudnicki M, César FA et al (2011) Anti-inflammatory and antioxidant properties of a new arylidene-thiazolidinedione in macrophages. Curr Med Chem 18:3351–3360

    Article  PubMed  CAS  Google Scholar 

  14. Choi JM, Bothwell AL (2012) The nuclear receptor PPARs as important regulators of T-cell functions and autoimmune diseases. Mol Cells 33:217–222

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  15. Cunard R, Eto Y, Muljadi JT et al (2004) Repression of IFN-γ expression by peroxisome proliferator-activated receptor γ. J Immunol 172:7530–7536

    Article  PubMed  CAS  Google Scholar 

  16. Housley WJ, Adams CO, Vang AG et al (2011) Peroxisome proliferator-activated receptor gamma is required for CD4 + T cell-mediated lymphopenia-associated autoimmunity. J Immunol 187:4161–4169

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  17. Yanagita M, Kobayashi R, Kojima Y et al (2012) Nicotine modulates the immunological function of dendritic cells through peroxisome proliferator-activated receptor-γ upregulation. Cell Immunol 274:26–33

    Article  PubMed  CAS  Google Scholar 

  18. Niino M (2007) Peroxisome proliferator-activated receptor agonists as potential therapeutic agents in multiple sclerosis. Mini Rev Med Chem 7:1129–1135

    Article  PubMed  CAS  Google Scholar 

  19. Peiris M, Monteith GR, Roberts-Thomson SJ et al (2007) A model of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice for the characterisation of intervention therapies. J Neurosci Methods 163:245–254

    Article  PubMed  CAS  Google Scholar 

  20. Hasegawa H, Takano H, Zou Y et al (2005) Pioglitazone, a peroxisome proliferator-activated receptor gamma activator, ameliorates experimental autoimmune myocarditis by modulating Th1/Th2 balance. J Mol Cell Cardiol 38:257–265

    Article  PubMed  CAS  Google Scholar 

  21. Yuan Z, Liu Y, Zhang J et al (2005) Cardioprotective effects of peroxisome proliferator activated receptor c activators on acute myocarditis: anti-inflammatory actions associated with nuclear factor κB blockade. Heart 91:1203–1208

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  22. Demerjian M, Man MQ, Choi EH et al (2006) Topical treatment with thiazolidinediones, activators of peroxisome proliferator-activated receptor-gamma, normalizes epidermal homeostasis in a murine hyperproliferative disease model. Exp Dermatol 15:154–160

    Article  PubMed  CAS  Google Scholar 

  23. Pershadsingh HA, Benson SC, Ellis CN (2005) Improvement in psoriasis with rosiglitazone in a diabetic and a nondiabetic patient. Skin med 4:386–390

    Article  Google Scholar 

  24. Schaefer KL, Denevich S, Ma C et al (2005) Intestinal antiinflammatory effects of thiazolidinedione peroxisome proliferator-activated receptor-gamma ligands on T helper type 1 chemokine regulation include nontranscriptional control mechanisms. Inflamm Bowel Dis 11:244–252

    Article  PubMed  Google Scholar 

  25. Buckingham RE (2005) Thiazolidinediones: pleiotropic drugs with potent anti-inflammatory properties for tissue protection. Hepatol Res 33:167–170

    Article  PubMed  CAS  Google Scholar 

  26. Pickup JC (2004) Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care 27:813–823

    Article  PubMed  Google Scholar 

  27. Donath MY, Storling J, Maedler K et al (2003) Inflammatory mediators and islet beta-cell failure. A link between type 1 and type 2 diabetes. J Mol Med 81:455–470

    Article  PubMed  CAS  Google Scholar 

  28. Gale EAM (2006) Declassifying diabetes. Diabetologia 49:1989–1995

    Article  PubMed  CAS  Google Scholar 

  29. Kurien BT, Scofield RH (2008) Autoimmunity and oxidatively modified autoantigens. Autoimmun Rev 7:567–573

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  30. Kurien BT, Hensley K, Bachmann M et al (2006) Oxidatively modified autoantigens in autoimmune diseases. Free Radic Biol Med 41:549–556

    Article  PubMed  CAS  Google Scholar 

  31. Ahmed N, Babaei-Jadidi R, Howell SK et al (2005) Degradation products of proteins damaged by glycation, oxidation and nitration in clinical type 1 diabetes. Diabetologia 48:1590–1603

    Article  PubMed  CAS  Google Scholar 

  32. Wang G, Li H, Firoze Khan M (2012) Differential oxidative modification of proteins in MRL+/+ and MRL/lpr mice: increased formation of lipid peroxidation-derived aldehyde-protein adducts may contribute to accelerated onset of autoimmune response. Free Radic Res 46:1472–1481

    Article  PubMed  CAS  Google Scholar 

  33. Tam LS, Shang Q, Li EK et al (2013) Serum soluble receptor for advanced glycation end products levels and aortic augmentation index in early rheumatoid arthritis-a prospective study. Semin Arthritis Rheum 42:333–345

    Article  PubMed  CAS  Google Scholar 

  34. Speidl WS, Kastl SP, Huber K et al (2011) Complement in atherosclerosis: friend or foe? J Thromb Haemost 9:428–440

    Article  PubMed  CAS  Google Scholar 

  35. Fosbrink M, Niculescu F, Rus V et al (2006) C5b-9-induced endothelial cell proliferation and migration are dependent on Akt inactivation of forkhead transcription factor FOXO1. J Biol Chem 281:19009–19018

    Article  PubMed  CAS  Google Scholar 

  36. Raquel H, William TH, Montse C et al (2011) Immunoregulatory mechanisms of macrophage PPAR γ in mice with experimental inflammatory bowel disease. Mucosal Immunol 4:304–313

    Article  CAS  Google Scholar 

  37. Zhang W, Eric AS, Paska AP et al (2008) Pioglitazone inhibits the expression of inflammatory cytokines from both monocytes and lymphocytes in patients with impaired glucose tolerance. Arterioscler Thromb Vasc Biol 28:2312–2318

    Article  PubMed  CAS  Google Scholar 

  38. Gao M, Hu Z, Zheng Y et al (2011) Peroxisome proliferator-activated receptor γ agonist troglitazone inhibits high mobility group box 1 expression in endothelial cells via suppressing transcriptional activity of nuclear factor κB and activator protein 1. Shock 36:228–234

    Article  PubMed  CAS  Google Scholar 

  39. Chen J, Mehta JL (2006) Angiotensin II-mediated oxidative stress and procollagen-1 expression in cardiac fibroblasts: blockade by pravastatin and pioglitazone. Am J Physiol Heart Circ Physiol 291:H1738–H1745

    Article  PubMed  CAS  Google Scholar 

  40. Ti Y, Hao MX, Li CB et al (2011) Rosiglitazone attenuates myocardial remodeling in spontaneously hypertensive rats. Hypertens Res 34:354–360

    Article  PubMed  CAS  Google Scholar 

  41. Straus DS, Glass CK (2007) Anti-inflammatory actions of PPAR ligands: new insights on cellular and molecular mechanisms. Trends Immunol 28:551–558

    Article  PubMed  CAS  Google Scholar 

  42. Chawla A, Barak Y, Nagy L et al (2001) PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat Med 7:48–52

    Article  PubMed  CAS  Google Scholar 

  43. Lee JH, Woo JH, Woo SU et al (2008) The 15-deoxy-delta 12,14-prostaglandin J2 suppresses monocyte chemoattractant protein-1 expression in IFN-gamma-stimulated astrocytes through induction of MAPK phosphatase-1. J Immunol 181:8642–8649

    Article  PubMed  CAS  Google Scholar 

  44. Asakawa M, Takano H, Nagai T et al (2002) Peroxisome proliferator-activated receptor gamma plays a critical role in inhibition of cardiac hypertrophy in vitro and in vivo. Circulation 105:1240–1246

    Article  PubMed  CAS  Google Scholar 

  45. Tsuji T, Mizushige K, Noma T et al (2001) Pioglitazone improves left ventricular diastolic function and decreases collagen accumulation in prediabetic stage of a type II diabetic rat. J Cardiovasc Pharmacol 38:868–874

    Article  PubMed  CAS  Google Scholar 

  46. Khandoudi N, Delerive P, Berrebi-Bertrand I, Buckingham RE, Staels B, Bril A (2002) Rosiglitazone, a peroxisome proliferator-activated receptorgamma, inhibits the Jun NH(2)-terminal kinase/activating protein 1 pathway and protects the heart from ischemia/reperfusion injury. Diabetes 51:1507–1514

    Article  PubMed  CAS  Google Scholar 

  47. Liu HR, Tao L, Gao E et al (2004) Anti-apoptotic effects of rosiglitazone in hypercholesterolemic rabbits subjected to myocardial ischemia and reperfusion. Cardiovasc Res 62:135–144

    Article  PubMed  CAS  Google Scholar 

  48. Dormandy JA, Charbonnel B, Eckland DJA et al (2005) PRO active investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitazone clinical trial in macro vascular events): a randomised controlled trial. Lancet 366:1279–1289

    Article  PubMed  CAS  Google Scholar 

  49. Derosa G (2010) Efficacy and tolerability of pioglitazone in patients with type 2 diabetes mellitus: comparison with other oral antihyperglycaemic agents. Drugs 70:1945–1961

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Grant support: Key Endocrine Laboratory of General Hospital and Animal Laboratory of Health Department of Tianjin Medical University. We thank Mr. WANG Yongming and Mrs. ZHANG Xinshi for helping with the care of the animals and technical aspects of this study.

Conflict of interest

M. Yuan, M. Qiu, J. Cui, X. Zhang, P. Zhang declare no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Endocrinology, General Hospital of Tianjin Medical University, Tianjin, 300052, China

    M. Yuan, M. Qiu & J. Cui

  2. Key Laboratory of Endocrinology, General Hospital of Tianjin Medical University, Tianjin, 300052, China

    X. Zhang & P. Zhang

Authors
  1. M. Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. X. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Qiu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yuan, M., Qiu, M., Cui, J. et al. Protective effects of pioglitazone against immunoglobulin deposition on heart of streptozotocin-induced diabetic rats. J Endocrinol Invest 37, 375–384 (2014). https://doi.org/10.1007/s40618-013-0046-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-013-0046-5

Keywords

Search

Navigation