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Horm Metab Res 2014; 46(01): 1-7
DOI: 10.1055/s-0033-1349090
Original Basic
© Georg Thieme Verlag KG Stuttgart · New York

Decrease of FGF Receptor (FGFR) and Interstitial Fibrosis in the Kidney of Streptozotocin-induced Diabetic Rats

M.-F. Cheng
1   Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan City, Taiwan
2   Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
,
L.-J. Chen
3   Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
,
M.-C. Wang
1   Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan City, Taiwan
4   Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
,
C.-T. Hsu
5   Department of Pathology, Edah University Medical Center, Yanchao, Kaohsiung City, Taiwan
,
J.-T. Cheng
3   Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
6   Department of Medical Research, Chi-Mei Medical Center, Yong Kang, Tainan City, Taiwan
› Author Affiliations
Further Information

Publication History

received 24 April 2013

accepted 05 June 2013

Publication Date:
04 July 2013 (online)

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Abstract

Fibrosis is the final disorder of end-stage renal disease. Activation of fibroblast growth factor (FGF) 23-klotho axis could suppress renal fibrosis in mice. Also, a marked decrease of klotho expression was observed in the kidney of streptozotocin-induced diabetic rats (STZ rats). However, relation of FGF in renal fibrosis remained unclear. This study was aimed to screen the effect of hyperglycemia on FGF receptor (FGFR) and fibrosis in kidney of rats with diabetic nephropathy and investigate this potential mechanism in cultured Madin-Darby Canine Kidney (MDCK) epithelial cells. STZ rats were used to treat with insulin or phloridzin at the dose sufficient to correct hyperglycemia for understanding the changes of renal dysfunction. The cultured MDCK cells were also used to treat with high glucose, hydrogen peroxide, or tiron in addition to transfection of siRNA to silence the klotho. Both insulin and phloridzin reversed fibrosis and FGFR expressions in kidney of STZ rats. It was confirmed in high glucose-exposed MDCK cells. However, klotho failed to modify the level of FGFR in MDCK cells. Meanwhile, FGFR was restored by tiron in MDCK cells and in diabetic rats without changing blood glucose. In conclusion, interstitial fibrosis and decreased FGFR expression are observed in the kidney of diabetic rats. This change is reversed by tiron without the correction of blood glucose. Also, klotho has no effect on expression of FGFR. Thus, decrease of oxidative stress is useful for the recovery of FGFR expression and improvement of renal fibrosis in type-1 like diabetic rats.

Key words

diabetic nephropathy - kidney fibrosis - FGFR - klotho - STZ rat
 

  • References

  • 1 Eddy AA. Molecular insights into renal interstitial fibrosis. J Am Soc Nephrol 1996; 7: 2495-2508
    PubMedGoogle Scholar
  • 2 el Nahas AM, Muchaneta-Kubara EC, Essawy M, Soylemezoglu O. Renal fibrosis: insights into pathogenesis and treatment. Int J Biochem Cell Biol 1997; 29: 55-62
    CrossrefPubMedGoogle Scholar
  • 3 Bohle A, Muller GA, Wehrmann M, Mackensen-Haen S, Xiao JC. Pathogenesis of chronic renal failure in the primary glomerulopathies, renal vasculopathies, and chronic interstitial nephritides. Kidney Inter Suppl 1996; 54: S2-S9
    PubMedGoogle Scholar
  • 4 Strutz F, Zeisberg M, Hemmerlein B, Sattler B, Hummel K, Becker V, Muller GA. Basic fibroblast growth factor expression is increased in human renal fibrogenesis and may mediate autocrine fibroblast proliferation. Kidney Int 2000; 57: 1521-1538
    CrossrefPubMedGoogle Scholar
  • 5 Kuro-o M. Klotho in chronic kidney disease – what's new?. Nephrol Dial Transplant 2009; 24: 1705-1708
    CrossrefPubMedGoogle Scholar
  • 6 Razzaque MS, Lanske B. The emerging role of the fibroblast growth factor-23-klotho axis in renal regulation of phosphate homeostasis. J Endocrinol 2007; 194: 1-10
    CrossrefPubMedGoogle Scholar
  • 7 Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, Baum MG, Schiavi S, Hu MC, Moe OW, Kuro-o M. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 2006; 281: 6120-6123
    CrossrefPubMedGoogle Scholar
  • 8 Cheng MF, Chen LJ, Cheng JT. Decrease of Klotho in the kidney of streptozotocin-induced diabetic rats. J Biomed Biotechnol 2010; 2010: 513853
    PubMedGoogle Scholar
  • 9 Laroche M, Boyer JF, Jahafar H, Allard J, Tack I. Normal FGF23 levels in adult idiopathic phosphate diabetes. Calcif Tissue Int 2009; 84: 112-117
    CrossrefPubMedGoogle Scholar
  • 10 Doi S, Zou Y, Togao O, Pastor JV, John GB, Wang L, Shiizaki K, Gotschall R, Schiavi S, Yorioka N, Takahashi M, Boothman DA, Kuro-o M. Klotho inhibits transforming growth factor-beta1 (TGF-beta1) signaling and suppresses renal fibrosis and cancer metastasis in mice. J Biol Chem 2011; 286: 8655-8665
    CrossrefPubMedGoogle Scholar
  • 11 Schena FP, Gesualdo L. Pathogenetic mechanisms of diabetic nephropathy. J Am Soc Nephrol 2005; 16 (Suppl. 01) S30-S33
    CrossrefPubMedGoogle Scholar
  • 12 Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, Kojima Y, Furuyoshi N, Shichiri M. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 1995; 28: 103-117
    CrossrefPubMedGoogle Scholar
  • 13 Shah SV, Baliga R, Rajapurkar M, Fonseca VA. Oxidants in chronic kidney disease. J Am Soc Nephrol 2007; 18: 16-28
    CrossrefPubMedGoogle Scholar
  • 14 Ohshiro Y, Takasu N. Molecular mechanism of diabetic nephropathy. Nippon Rinsho 2006; 64: 997-1003
    PubMedGoogle Scholar
  • 15 Ha H, Lee HB. Reactive oxygen species amplify glucose signalling in renal cells cultured under high glucose and in diabetic kidney. Nephrology (Carlton) 2005; 10 (Suppl) S7-S10
    CrossrefPubMedGoogle Scholar
  • 16 Campanholle G, Ligestri G, Gharib SA, Duffield JS. Cellular Mechanisms of Tissue Fibrosis. 3. Novel mechanisms of kidney fibrosis. Am J Physiol Cell Physiol 2013; DOI: 10.1152/ajpcell.00414.2012.
    PubMedGoogle Scholar
  • 17 Cheng JT, Huang CC, Liu IM, Tzeng TF, Chang CJ. Novel mechanism for plasma glucose-lowering action of metformin in streptozotocin-induced diabetic rats. Diabetes 2006; 55: 819-825
    CrossrefPubMedGoogle Scholar
  • 18 Yeh CH, Chang CK, Cheng MF, Lin HJ, Cheng JT. Decrease of bone morphogenetic protein-7 (BMP-7) and its type II receptor (BMP-RII) in kidney of type 1-like diabetic rats. Horm Metab Res 2009; 41: 605-611
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Zhang H, Li Y, Fan Y, Wu J, Zhao B, Guan Y, Chien S, Wang N.. Klotho is a target gene of PPAR-gamma. Kidney Int 2008; 74: 732-739
    CrossrefPubMedGoogle Scholar
  • 20 Huang CJ, Liu IM, Cheng JT. Increase of peroxisome proliferator-activated receptor delta gene expression in the lungs of streptozotocin-induced diabetic rats. Pulm Pharmacol Ther 2007; 20: 69-74
    CrossrefPubMedGoogle Scholar
  • 21 Hsieh TJ, Zhang SL, Filep JG, Tang SS, Ingelfinger JR, Chan JS. High glucose stimulates angiotensinogen gene expression via reactive oxygen species generation in rat kidney proximal tubular cells. Endocrinology 2002; 143: 2975-2985
    CrossrefPubMedGoogle Scholar
  • 22 Iglesias-De La Cruz MC, Ruiz-Torres P, Alcami J, Diez-Marques L, Ortega-Velazquez R, Chen S, Rodriguez-Puyol M, Ziyadeh FN, Rodriguez-Puyol D. Hydrogen peroxide increases extracellular matrix mRNA through TGF-beta in human mesangial cells. Kidney Int 2001; 59: 87-95
    CrossrefPubMedGoogle Scholar
  • 23 Mauer SM, Steffes MW, Brown DM. The kidney in diabetes. Am J Med 1981; 70: 603-612
    CrossrefPubMedGoogle Scholar
  • 24 Hawkins M, Hu M, Yu J, Eder H, Vuguin P, She L, Barzilai N, Leiser M, Backer JM, Rossetti L. Discordant effects of glucosamine on insulin-stimulated glucose metabolism and phosphatidylinositol 3-kinase activity. J Biol Chem 1999; 274: 31312-31319
    CrossrefPubMedGoogle Scholar
  • 25 Rossini M, Cheunsuchon B, Donnert E, Ma LJ, Thomas JW, Neilson EG, Fogo AB. Immunolocalization of fibroblast growth factor-1 (FGF-1), its receptor (FGFR-1), and fibroblast-specific protein-1 (FSP-1) in inflammatory renal disease. Kidney Int 2005; 68: 2621-2628
    CrossrefPubMedGoogle Scholar
  • 26 Han YH, Park WH. Tiron, a ROS scavenger, protects human lung cancer Calu-6 cells against antimycin A-induced cell death. Oncol Rep 2009; 21: 253-261
    PubMedGoogle Scholar