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

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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.

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References

  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)

    Article  PubMed  CAS  Google Scholar 

  2. T.A. Wynn, Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J. Clin. Invest. 117, 524–529 (2007)

    Article  PubMed  CAS  Google Scholar 

  3. Min Heun Cho, M.D. Korean, J Pediatr Renal fibrosis. Korean J. Pediatr. 53, 735–740 (2010)

    Article  PubMed  Google Scholar 

  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)

    Article  PubMed  CAS  Google Scholar 

  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)

    Article  PubMed  CAS  Google Scholar 

  6. W.S. To, K.S. Midwood, Cryptic domains of tenascin-C differentially control fibronectin fibrillogenesis. Matrix Biol. 29, 573–585 (2010)

    Article  PubMed  CAS  Google Scholar 

  7. G.S. Schultz, A. Wysocki, Interactions between extracellular matrix and growth factors in wound healing. Wound Repair Regen. 17, 153–162 (2009)

    Article  PubMed  Google Scholar 

  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)

    Article  PubMed  CAS  Google Scholar 

  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)

    Article  PubMed  CAS  Google Scholar 

  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. 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)

    Article  PubMed  CAS  Google Scholar 

  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)

    PubMed  CAS  Google Scholar 

  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)

    Article  PubMed  CAS  Google Scholar 

  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)

    Article  PubMed  CAS  Google Scholar 

  15. Vasilios Berdoukas, Kallistheni Farmaki, Susan Carson, Treating thalassemia major-related iron overload: the role of deferiprone. J Blood Med. 3, 119–129 (2012)

    Article  PubMed  CAS  Google Scholar 

  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)

    Article  PubMed  CAS  Google Scholar 

  17. Sudhihr V. Shah, Mohan M. Rajapurkar, The role of labile iron in kidney disease and treatment with chelation. Hemoglobin 33, 378–385 (2009)

    Article  PubMed  CAS  Google Scholar 

  18. Ying Li, Qiong Chen, Fu-You Liu, Norcantharidin attenuates tubulointerstitial fibrosis in rat models with diabetic nephropathy. Ren. Fail. 33, 233–241 (2011)

    Article  PubMed  CAS  Google Scholar 

  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)

    Article  PubMed  CAS  Google Scholar 

  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)

    Article  PubMed  CAS  Google Scholar 

  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)

    Article  PubMed  Google Scholar 

  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)

    Article  PubMed  CAS  Google Scholar 

  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)

    Article  PubMed  CAS  Google Scholar 

  24. G. Abbruzzese, G. Cossu, M. Balocco, A pilot trial of deferiprone for neurodegeneration with brain iron accumulation. Haematologica 96, 1708–1711 (2011)

    Article  PubMed  CAS  Google Scholar 

  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)

    Article  PubMed  CAS  Google Scholar 

  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)

    PubMed  CAS  Google Scholar 

  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)

    Article  PubMed  CAS  Google Scholar 

  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)

    Article  PubMed  CAS  Google Scholar 

  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)

    Article  PubMed  Google Scholar 

  30. A. Inada, K. Nagai, H. Arai, Establishment of a diabetic mouse model with progressive diabetic nephropathy. Am. J. Pathol. 167, 327–336 (2005)

    Article  PubMed  Google Scholar 

  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)

    Article  PubMed  CAS  Google Scholar 

  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)

    PubMed  CAS  Google Scholar 

  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)

    Article  PubMed  CAS  Google Scholar 

  34. T. Pantsulaia, Role of TGF-beta in pathogenesis of diabetic nephropathy. Georgian Med. News. 131, 13–18 (2006)

    PubMed  Google Scholar 

  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)

    Article  PubMed  CAS  Google Scholar 

  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)

    Article  PubMed  CAS  Google Scholar 

  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)

    Article  PubMed  CAS  Google Scholar 

  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)

    Article  PubMed  CAS  Google Scholar 

  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)

    Article  PubMed  CAS  Google Scholar 

  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)

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by Natural Science Foundation of Heilongjiang Province, China (D201083).

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  None of the authors has any potential conflicts of interest to declare.

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Authors and Affiliations

  1. Department of Nephrology, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Str, Nangang District, Harbin, People’s Republic of China

    Chunbo Zou, Rujuan Xie, Yushi Bao, Xiaogang Liu, Manshu Sui, Suhong M & Shuang Li

  2. Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Str, Nangang District, Harbin, People’s Republic of China

    Huiqing Yin

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  1. Chunbo Zou
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  2. Rujuan Xie
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  3. Yushi Bao
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Zou, C., Xie, R., Bao, Y. et al. Iron chelator alleviates tubulointerstitial fibrosis in diabetic nephropathy rats by inhibiting the expression of tenascinC and other correlation factors. Endocrine 44, 666–674 (2013). https://doi.org/10.1007/s12020-013-9907-0

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  • DOI: https://doi.org/10.1007/s12020-013-9907-0

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