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

M.-F. Cheng; L.-J. Chen; M.-C. Wang; C.-T. Hsu; J.-T. Cheng

doi:10.1055/s-0033-1349090

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2014; 46(01): 1-7
DOI: 10.1055/s-0033-1349090

Original Basic

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

M.-F. Cheng

¹Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan City, Taiwan

²Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan City, Taiwan

,

L.-J. Chen

³Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan City, Taiwan

,

M.-C. Wang

¹Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan City, Taiwan

⁴Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan City, Taiwan

,

C.-T. Hsu

⁵Department of Pathology, Edah University Medical Center, Yanchao, Kaohsiung City, Taiwan

,

J.-T. Cheng

³Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan City, Taiwan

⁶Department of Medical Research, Chi-Mei Medical Center, Yong Kang, Tainan City, Taiwan

› Author Affiliations

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

Full Text

References

References
1 Eddy AA. Molecular insights into renal interstitial fibrosis. J Am Soc Nephrol 1996; 7: 2495-2508
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
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
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
5 Kuro-o M. Klotho in chronic kidney disease – what's new?. Nephrol Dial Transplant 2009; 24: 1705-1708
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
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
8 Cheng MF, Chen LJ, Cheng JT. Decrease of Klotho in the kidney of streptozotocin-induced diabetic rats. J Biomed Biotechnol 2010; 2010: 513853
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
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
11 Schena FP, Gesualdo L. Pathogenetic mechanisms of diabetic nephropathy. J Am Soc Nephrol 2005; 16 (Suppl. 01) S30-S33
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
13 Shah SV, Baliga R, Rajapurkar M, Fonseca VA. Oxidants in chronic kidney disease. J Am Soc Nephrol 2007; 18: 16-28
14 Ohshiro Y, Takasu N. Molecular mechanism of diabetic nephropathy. Nippon Rinsho 2006; 64: 997-1003
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
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;
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
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
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
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
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
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
23 Mauer SM, Steffes MW, Brown DM. The kidney in diabetes. Am J Med 1981; 70: 603-612
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
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
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