Iron chelator alleviates tubulointerstitial fibrosis in diabetic nephropathy rats by inhibiting the expression of tenascinC and other correlation factors Authors
First Online: 07 March 2013 Received: 08 September 2012 Accepted: 13 February 2013 DOI:
Cite this article as: Zou, C., Xie, R., Bao, Y. et al. Endocrine (2013) 44: 666. doi:10.1007/s12020-013-9907-0 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
R.E. Gilbert, M.E. Cooper, The tubulointerstitium in progressive diabetic kidney disease: More than an aftermath of glomerular injury? Kidney Int.
, 1627–1637 (1999)
T.A. Wynn, Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J. Clin. Invest.
, 524–529 (2007)
Min Heun Cho, M.D. Korean, J Pediatr Renal fibrosis. Korean J. Pediatr.
, 735–740 (2010)
F.N. Ziyadeh, Mediators of diabetic renal disease: the case for TGF-β as the major mediator. J. Am. Soc. Nephrol.
, S55–S57 (2004)
G. Remuzzi, A. Benigni, A. Remuzzi, Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J. Clin. Invest.
, 288–296 (2006)
W.S. To, K.S. Midwood, Cryptic domains of tenascin-C differentially control fibronectin fibrillogenesis. Matrix Biol.
, 573–585 (2010)
G.S. Schultz, A. Wysocki, Interactions between extracellular matrix and growth factors in wound healing. Wound Repair Regen.
, 153–162 (2009)
M. Hadziahmetovic, Y. Song, N. Wolkow, The oral iron chelator deferiprone protects against iron overload–induced retinal degeneration. Invest. Ophthalmol. Vis. Sci.
(2), 959–968 (2011)
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.
, 201–206 (2010)
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)
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.
(11), 2192–2201 (2012)
B.J. Nankivell, J. Chen, R.A. Boadle, The role of tubular iron accumulation in the remnant kidney. J. Am. Soc. Nephrol.
, 1598–1607 (1994)
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
, 949–956 (2007)
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
, 17–21 (2002)
Vasilios Berdoukas, Kallistheni Farmaki, Susan Carson, Treating thalassemia major-related iron overload: the role of deferiprone. J Blood Med.
, 119–129 (2012)
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
(1–2), 88–94 (2012)
Sudhihr V. Shah, Mohan M. Rajapurkar, The role of labile iron in kidney disease and treatment with chelation. Hemoglobin
, 378–385 (2009)
Ying Li, Qiong Chen, Fu-You Liu, Norcantharidin attenuates tubulointerstitial fibrosis in rat models with diabetic nephropathy. Ren. Fail.
, 233–241 (2011)
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.
(7), 477–484 (2006)
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.
, 375–384 (2010)
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.
, 80–87 (2010)
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.
, 1805–1818 (2011)
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
, 460–469 (2008)
G. Abbruzzese, G. Cossu, M. Balocco, A pilot trial of deferiprone for neurodegeneration with brain iron accumulation. Haematologica
, 1708–1711 (2011)
D.S. Kalinowski, D.R. Richardson, The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer. Pharmacol. Rev.
, 547–583 (2005)
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.
, 1598–1607 (1994)
D.C. Harris, C. Tay, B.J. Nankivell, Lysosomal iron accumulation and tubular damage in rat puromycin nephrosis and ageing. Clin. Exp. Pharmacol. Physiol.
, 73–81 (1994)
S. Fujimoto, N. Kawakami, A. Ohara, Nonenzymatic glycation of transferrin: decrease of Iron-binding capacity and increase of oxygen radical production. Biol. Pharm. Bull.
, 396–400 (1995)
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
, 185–194 (2004)
A. Inada, K. Nagai, H. Arai, Establishment of a diabetic mouse model with progressive diabetic nephropathy. Am. J. Pathol.
, 327–336 (2005)
Y. Sun, J. Zhang, J.Q. Zhang, Local angiotensin II and transforming growth factor-beta1 in renal fibrosis of rats. Hypertension
(5), 1078–1084 (2000)
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.
(1), F59–F67 (2003)
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.
(2), 123–128 (2004)
T. Pantsulaia, Role of TGF-beta in pathogenesis of diabetic nephropathy. Georgian Med. News.
, 13–18 (2006)
Y. Nishitani, M. Iwano, Y. Yamaguchi, Fibroblast-specific protein 1 is a specific prognostic marker for renal survival in patients with IgAN. Kidney Int.
, 1078–1085 (2005)
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.
, 43000–43009 (2005)
M. Jinnin, H. Ihn, Y. Asano, Tenascin-C upregulation by transforming growth factor-beta in human dermal fibroblasts involves. Oncogene
, 1656–1667 (2004)
Y. Gorin, K. Block, J. Hernandez, Nox4 NAD(P)H Oxidase Mediates Hypertrophy and Fibronectin Expression in the Diabetic Kidney. J. Biol. Chem.
(47), 39616–39626 (2005)
A. El-Karef, T. Yoshida, E.C. Gabazza, Deficiency of tenascin-C attenuates liver fibrosis in immune-mediated chronic hepatitis in mice. J. Pathol.
(1), 86–94 (2007)
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.
(6), L785–L793 (2010)
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