Endocrine

, Volume 44, Issue 3, pp 666–674 | Cite as

Iron chelator alleviates tubulointerstitial fibrosis in diabetic nephropathy rats by inhibiting the expression of tenascinC and other correlation factors

  • Chunbo Zou
  • Rujuan Xie
  • Yushi Bao
  • Xiaogang Liu
  • Manshu Sui
  • Suhong M
  • Shuang Li
  • Huiqing Yin
Original Article

Abstract

Tubulointerstitial fibrosis is the final common pathway to diabetic nephropathy. However, only a few drugs are responsible for this pathologic process. We investigated the possible effect of deferiprone (iron chelator) treatment on experimental diabetic nephropathy (DN) rats, as well as the mechanisms involved in this process. Diabetic nephropathy was induced in rats by feeding on high-carbohydrate–fat food and injecting streptozotocin. After 20 weeks of deferiprone treatment, tubulointerstitial morphology was detected by staining with hematoxylin–eosin and Masson’s trichrome. Tubulointerstitial fibrosis was measured using the point-counting technique. Biochemical parameters including fasting glucose, insulin resistance (IR), serum iron, ferritin, transferrin saturation (TS), and urinary albumin/creatinine ratio (UA/C) were detected in diabetic nephropathy models. Semiquantitative RT-PCR, western blot, and immunohistochemistry were utilized for evaluating mRNA and protein levels of tenascin C, fibronectin 1 (Fn1), TGF-β1, and collagen IV in nephridial tissue, respectively. Malonialdehyde (MDA) and superoxide dismutase (SOD) were determined by pyrogallol and thiobarbituric acid method. Tubulointerstitial fibrosis was significantly ameliorated after deferiprone treatment, and both mRNA and protein expressions of profibrotic factors were inhibited in treatment groups. Meanwhile, high levels of serum iron, ferritin, TS, and UA/C were observed in DN rats. These factors were down-regulated by deferiprone treatment. Furthermore, deferiprone effectively relieved serum IR and regulated oxidative stress process. Our results demonstrated the anti-fibrosis potential and renoprotective effects of deferiprone for diabetic nephropathy, and this process was partially mediated by tenascin C blocking.

Keywords

Iron-chelator Diabetic nephropathy Tubulointerstitial fibrosis TenascinC 

References

  1. 1.
    R.E. Gilbert, M.E. Cooper, The tubulointerstitium in progressive diabetic kidney disease: More than an aftermath of glomerular injury? Kidney Int. 56, 1627–1637 (1999)PubMedCrossRefGoogle Scholar
  2. 2.
    T.A. Wynn, Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J. Clin. Invest. 117, 524–529 (2007)PubMedCrossRefGoogle Scholar
  3. 3.
    Min Heun Cho, M.D. Korean, J Pediatr Renal fibrosis. Korean J. Pediatr. 53, 735–740 (2010)PubMedCrossRefGoogle Scholar
  4. 4.
    F.N. Ziyadeh, Mediators of diabetic renal disease: the case for TGF-β as the major mediator. J. Am. Soc. Nephrol. 15, S55–S57 (2004)PubMedCrossRefGoogle Scholar
  5. 5.
    G. Remuzzi, A. Benigni, A. Remuzzi, Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J. Clin. Invest. 116, 288–296 (2006)PubMedCrossRefGoogle Scholar
  6. 6.
    W.S. To, K.S. Midwood, Cryptic domains of tenascin-C differentially control fibronectin fibrillogenesis. Matrix Biol. 29, 573–585 (2010)PubMedCrossRefGoogle Scholar
  7. 7.
    G.S. Schultz, A. Wysocki, Interactions between extracellular matrix and growth factors in wound healing. Wound Repair Regen. 17, 153–162 (2009)PubMedCrossRefGoogle Scholar
  8. 8.
    M. Hadziahmetovic, Y. Song, N. Wolkow, The oral iron chelator deferiprone protects against iron overload–induced retinal degeneration. Invest. Ophthalmol. Vis. Sci. 52(2), 959–968 (2011)PubMedCrossRefGoogle Scholar
  9. 9.
    G.J. Kontoghiorghes, A. Kolnagou, C.T. Peng, Safety issues of iron chelation therapy in patients with normal range iron stores including thalassaemia, neurodegenerative, renal and infectious diseases. Expert Opin. Drug. Saf. 9, 201–206 (2010)PubMedCrossRefGoogle Scholar
  10. 10.
    B.J. Nankivell, R.A. Boadle, D.C.H. Harris, Iron accumulation in human chronic renal disease. Am. J. Kidney Dis. 20, 504–580 (1992)Google Scholar
  11. 11.
    Y. Naito, A. Fujii, H. Sawada, Effect of iron restriction on renal damage and mineralocorticoid receptor signaling in a rat model of chronic kidney disease. J. Hypertens. 30(11), 2192–2201 (2012)PubMedCrossRefGoogle Scholar
  12. 12.
    B.J. Nankivell, J. Chen, R.A. Boadle, The role of tubular iron accumulation in the remnant kidney. J. Am. Soc. Nephrol. 4, 1598–1607 (1994)PubMedGoogle Scholar
  13. 13.
    N.G. Forouhi, A.H. Harding, Allison M, Elevated serum ferritin levels predict new-onset type 2 diabetes: results from the EPIC-Norfolk prospective study. Diabetologia 50, 949–956 (2007)PubMedCrossRefGoogle Scholar
  14. 14.
    Emanuele Angelucci, Pietro Muretto, Antonio Nicolucci, Effects of iron overload and hepatitis C virus positivity in determining progression of liver fibrosis in thalassemia following bone marrow transplantation. Blood 100, 17–21 (2002)PubMedCrossRefGoogle Scholar
  15. 15.
    Vasilios Berdoukas, Kallistheni Farmaki, Susan Carson, Treating thalassemia major-related iron overload: the role of deferiprone. J Blood Med. 3, 119–129 (2012)PubMedCrossRefGoogle Scholar
  16. 16.
    S. Rodrat, P. Yamanont, J. Tankanitlert, Comparison of pharmacokinetics and urinary iron excretion of two single doses of deferiprone in β-thalassemia/hemoglobin E patients. Pharmacology 90(1–2), 88–94 (2012)PubMedCrossRefGoogle Scholar
  17. 17.
    Sudhihr V. Shah, Mohan M. Rajapurkar, The role of labile iron in kidney disease and treatment with chelation. Hemoglobin 33, 378–385 (2009)PubMedCrossRefGoogle Scholar
  18. 18.
    Ying Li, Qiong Chen, Fu-You Liu, Norcantharidin attenuates tubulointerstitial fibrosis in rat models with diabetic nephropathy. Ren. Fail. 33, 233–241 (2011)PubMedCrossRefGoogle Scholar
  19. 19.
    M. Sugano, H. Yamato, T. Hayashi, High-fat diet inlow-dose-streptozotocin-treated heminephrectomized rats induces all features of human type 2 diabetic nephropathy: a new rat model of diabetic nephropathy. Nutr. Metab. Cardiovasc. Dis. 16(7), 477–484 (2006)PubMedCrossRefGoogle Scholar
  20. 20.
    Chi Young Shim, Sungha Park, Jung-Sun Kim, Association of plasma retinol-binding protein 4, adiponectin, and high molecular weight adiponectin with insulin resistance in non-diabetic hypertensive patients. Yonsei Med. J. 51, 375–384 (2010)PubMedCrossRefGoogle Scholar
  21. 21.
    T.A. O’Sullivan, A.P. Bremner, S. O’Neill, Glycemic load is associated with insulin resistance in older Australian women. Eur. J. Clin. Nutr. 64, 80–87 (2010)PubMedCrossRefGoogle Scholar
  22. 22.
    J.W.Tang Meng, Y. Wang, Astragaloside IV synergizes with ferulic acid to inhibit renal tubulointerstitial fibrosis in rats with obstructive nephropathy LQ. Br. J. Pharmacol. 162, 1805–1818 (2011)PubMedCrossRefGoogle Scholar
  23. 23.
    V. Thallas-Bonke, S.R. Thorpe, T. Melinda, Inhibition of NADPH Oxidase Prevents Advanced Glycation End Product–Mediated Damage in Diabetic Nephropathy Through a Protein Kinase C-α–Dependent Pathway. Diabetes 57, 460–469 (2008)PubMedCrossRefGoogle Scholar
  24. 24.
    G. Abbruzzese, G. Cossu, M. Balocco, A pilot trial of deferiprone for neurodegeneration with brain iron accumulation. Haematologica 96, 1708–1711 (2011)PubMedCrossRefGoogle Scholar
  25. 25.
    D.S. Kalinowski, D.R. Richardson, The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer. Pharmacol. Rev. 57, 547–583 (2005)PubMedCrossRefGoogle Scholar
  26. 26.
    B.J. Nankivell, J. Chen, R.A. Boadle, D.C.H. Harris, The role of tubular iron accumulation in the remnant kidney. J. Am. Soc. Nephrol. 4, 1598–1607 (1994)PubMedGoogle Scholar
  27. 27.
    D.C. Harris, C. Tay, B.J. Nankivell, Lysosomal iron accumulation and tubular damage in rat puromycin nephrosis and ageing. Clin. Exp. Pharmacol. Physiol. 21, 73–81 (1994)PubMedCrossRefGoogle Scholar
  28. 28.
    S. Fujimoto, N. Kawakami, A. Ohara, Nonenzymatic glycation of transferrin: decrease of Iron-binding capacity and increase of oxygen radical production. Biol. Pharm. Bull. 18, 396–400 (1995)PubMedCrossRefGoogle Scholar
  29. 29.
    D.H. Lee, A.R. Folsom, D.R.J. Jacobs, Dietary iron intake and type 2 diabetes incidence in postmenopausal women: the Iowa Women’s Health Study. Diabetologia 47, 185–194 (2004)PubMedCrossRefGoogle Scholar
  30. 30.
    A. Inada, K. Nagai, H. Arai, Establishment of a diabetic mouse model with progressive diabetic nephropathy. Am. J. Pathol. 167, 327–336 (2005)PubMedCrossRefGoogle Scholar
  31. 31.
    Y. Sun, J. Zhang, J.Q. Zhang, Local angiotensin II and transforming growth factor-beta1 in renal fibrosis of rats. Hypertension 35(5), 1078–1084 (2000)PubMedCrossRefGoogle Scholar
  32. 32.
    G.A. McDonald, P. Sarkar, H. Rennke, Relaxin increases ubiquitin-dependent degradation of fibronectin in vitro and ameliorates renal fibrosis in vivo. Am. J. Physiol. Renal. Physiol. 285(1), F59–F67 (2003)PubMedGoogle Scholar
  33. 33.
    K. Uchio, N. Manabe, M. Yamaguchi-Yamada, Changes in the localization of type I, III and IV collagen mRNAs in the kidneys of hereditary nephritic (ICGN) mice with renal fibrosis. J. Vet. Med. Sci. 66(2), 123–128 (2004)PubMedCrossRefGoogle Scholar
  34. 34.
    T. Pantsulaia, Role of TGF-beta in pathogenesis of diabetic nephropathy. Georgian Med. News. 131, 13–18 (2006)PubMedGoogle Scholar
  35. 35.
    Y. Nishitani, M. Iwano, Y. Yamaguchi, Fibroblast-specific protein 1 is a specific prognostic marker for renal survival in patients with IgAN. Kidney Int. 68, 1078–1085 (2005)PubMedCrossRefGoogle Scholar
  36. 36.
    N. Khalil, Y.D. Xu, R. O’Connor, Proliferation of pulmonary interstitial fibroblasts is mediated by transforming growth factor-beta1-induced release of extracellular fibroblast growth factor-2 and phosphorylation of p38 MAPK and JNK. J. Biol. Chem. 280, 43000–43009 (2005)PubMedCrossRefGoogle Scholar
  37. 37.
    M. Jinnin, H. Ihn, Y. Asano, Tenascin-C upregulation by transforming growth factor-beta in human dermal fibroblasts involves. Oncogene 23, 1656–1667 (2004)PubMedCrossRefGoogle Scholar
  38. 38.
    Y. Gorin, K. Block, J. Hernandez, Nox4 NAD(P)H Oxidase Mediates Hypertrophy and Fibronectin Expression in the Diabetic Kidney. J. Biol. Chem. 280(47), 39616–39626 (2005)PubMedCrossRefGoogle Scholar
  39. 39.
    A. El-Karef, T. Yoshida, E.C. Gabazza, Deficiency of tenascin-C attenuates liver fibrosis in immune-mediated chronic hepatitis in mice. J. Pathol. 211(1), 86–94 (2007)PubMedCrossRefGoogle Scholar
  40. 40.
    W.A. Carey, G.D. Taylor, W.B. Dean, Tenascin-C deficiency attenuates TGF-ß-mediated fibrosis following murine lung injury. Am. J. Physiol. Lung Cell. Mol. Physiol. 299(6), L785–L793 (2010)PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Chunbo Zou
    • 1
  • Rujuan Xie
    • 1
  • Yushi Bao
    • 1
  • Xiaogang Liu
    • 1
  • Manshu Sui
    • 1
  • Suhong M
    • 1
  • Shuang Li
    • 1
  • Huiqing Yin
    • 2
  1. 1.Department of NephrologyThe First Affiliated Hospital of Harbin Medical UniversityNangang District, HarbinPeople’s Republic of China
  2. 2.Department of EndocrinologyThe First Affiliated Hospital of Harbin Medical UniversityNangang District, HarbinPeople’s Republic of China

Personalised recommendations