Download PDF
Horm Metab Res 2016; 48(09): 613-619
DOI: 10.1055/s-0042-108448
Endocrine Research
© Georg Thieme Verlag KG Stuttgart · New York

Protective Role of PEDF-Derived Synthetic Peptide Against Experimental Diabetic Nephropathy

Y. Ishibashi
1   Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
,
T. Matsui
1   Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
,
J. Taira
2   Department of Chemistry, Kurume University School of Medicine, Kurume, Japan
,
Y. Higashimoto
2   Department of Chemistry, Kurume University School of Medicine, Kurume, Japan
,
S. Yamagishi
1   Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
› Author Affiliations
Further Information

Publication History

received 12 February 2016

accepted 04 May 2016

Publication Date:
23 May 2016 (online)

Also available at
    Permissions and Reprints

Abstract

Pigment epithelium-derived factor (PEDF) is a glycoprotein with complex neuroprotective, anti-angiogenic, and anti-inflammatory properties, all of which could potentially be exploited as a therapeutic option for vascular complications in diabetes. We have previously shown that PEDF-derived synthetic peptide, P5-3 (FIFVLRD) has a comparable ability with full PEDF protein to inhibit rat corneal neovascularization induced by chemical cauterization. However, the effects of PEDF peptide on experimental diabetic nephropathy remain unknown. To address the issue, we modified P5-3 to stabilize and administered the modified peptide (d-Lys-d-Lys-d-Lys-Gln-d-Pro-P5-3-Cys-amide, 0.2 nmol/day) or vehicle to streptozotocin-induced diabetic rats (STZ-rats) intraperitoneally by an osmotic mini pump for 2 weeks. We further examined the effects of modified peptide on human proximal tubular cells. Renal PEDF expression was decreased in STZ-rats. Although the peptide administration did not affect blood glucose or blood pressure, it decreased urinary excretion levels of 8-hydroxy-2′-deoxyguanosine, an oxidative stress marker, and reduced plasminogen activator inhibitor-1 (PAI-1) gene expression, and suppressed glomerular expansion in the diabetic kidneys. High glucose or advanced glycation end products stimulated oxidative stress generation and PAI-1 gene expression in tubular cells, all of which were significantly suppressed by 10 nM modified P5-3 peptide. Our present study suggests that PEDF-derived synthetic modified peptide could protect against experimental diabetic nephropathy and inhibit tubular cell damage under diabetes-like conditions through its anti-oxidative properties. Supplementation of modified P5-3 peptide may be a novel therapeutic strategy for diabetic nephropathy.

Key words

AGEs - oxidative stress - PEDF - diabetic nephropathy - RAGE
 

  • References

  • 1 International Diabetes Federation . IDF Diabetes Atlas. 7th edition, revision 2015 Brussels, Belgium: International Diabetes Federation; 2015
    Google Scholar
  • 2 Yamagishi S, Imaizumi T. Diabetic vascular complications: pathophysiology, biochemical basis and potential therapeutic strategy. Curr Pharm Des 2005; 11: 2279-2299
    CrossrefPubMedGoogle Scholar
  • 3 Yamagishi S, Fukami K, Ueda S, Okuda S. Molecular mechanisms of diabetic nephropathy and its therapeutic intervention. Curr Drug Targets 2007; 8: 952-959
    CrossrefPubMedGoogle Scholar
  • 4 Taft JL, Nolan CJ, Yeung SP, Hewitson TD, Martin FI. Clinical and histological correlations of decline in renal function in diabetic patients with proteinuria. Diabetes 1994; 43: 1046-1051
    CrossrefPubMedGoogle Scholar
  • 5 Ziyadeh FN, Goldfarb S. The renal tubulointerstitium in diabetes mellitus. Kidney Int 1991; 39: 464-475
    CrossrefPubMedGoogle Scholar
  • 6 Sourris KC, Forbes JM, Cooper ME. Therapeutic interruption of advanced glycation in diabetic nephropathy: do all roads lead to Rome?. Ann NY Acad Sci 2008; 1126: 101-106
    CrossrefPubMedGoogle Scholar
  • 7 Vlassara H, Torreggiani M, Post JB, Zheng F, Uribarri J, Striker GE. Role of oxidants/inflammation in declining renal function in chronic kidney disease and normal aging. Kidney Int Suppl 2009; 114: S3-S11
    PubMedGoogle Scholar
  • 8 Ojima A, Ishibashi Y, Matsui T, Maeda S, Nishino Y, Takeuchi M, Fukami K, Yamagishi S. Glucagon-like peptide-1 receptor agonist inhibits asymmetric dimethylarginine generation in the kidney of streptozotocin-induced diabetic rats by blocking advanced glycation end product-induced protein arginine methyltranferase-1 expression. Am J Pathol 2013; 182: 132-141
    CrossrefPubMedGoogle Scholar
  • 9 Kaida Y, Fukami K, Matsui T, Higashimoto Y, Nishino Y, Obara N, Nakayama Y, Ando R, Toyonaga M, Ueda S, Takeuchi M, Inoue H, Okuda S, Yamagishi S. DNA aptamer raised against AGEs blocks the progression of experimental diabetic nephropathy. Diabetes 2013; 62: 3241-3250
    CrossrefPubMedGoogle Scholar
  • 10 Ishibashi Y, Matsui T, Ohta K, Tanoue R, Takeuchi M, Asanuma K, Fukami K, Okuda S, Nakamura K, Yamagishi S. PEDF inhibits AGE-induced podocyte apoptosis via PPAR-gamma activation. Microvasc Res 2013; 85: 54-58
    CrossrefPubMedGoogle Scholar
  • 11 Manigrasso MB, Juranek J, Ramasamy R, Schmidt AM. Unlocking the biology of RAGE in diabetic microvascular complications. Trends Endocrinol Metab 2014; 25: 15-22
    CrossrefPubMedGoogle Scholar
  • 12 Tombran-Tink J, Chader CG, Johnson LV. PEDF: a pigment epithelium-derived factor with potent neuronal differentiative activity. Exp Eye Res 1991; 53: 411-414
    CrossrefPubMedGoogle Scholar
  • 13 Dawson DW, Volpert OV, Gillis P, Crawford SE, Xu HJ, Benedict W, Bouck NP. Pigment epithelium-derived factor: A potent inhibitor of angiogenesis. Science 1999; 285: 245-248
    CrossrefPubMedGoogle Scholar
  • 14 Duh EJ, Yang HS, Suzuma I, Miyagi M, Youngman E, Mori K, Katai M, Yan L, Suzuma K, West K, Davarya S, Tong P, Gehlbach P, Pearlman J, Crabb JW, Aiello LP, Campochiaro PA, Zack DJ. Pigment epithelium-derived factor suppresses ischemia-induced retinal neovascularization and VEGF-induced migration and growth. Invest Ophthalmol Vis Sci 2002; 43: 821-829
    PubMedGoogle Scholar
  • 15 Tombran-Tink J, Barnstable CJ. PEDF: a multifaceted neurotrophic factor. Nat Rev Neurosci 2003; 4: 628-636
    CrossrefPubMedGoogle Scholar
  • 16 Nakashima S, Matsui T, Yamagishi S. Pigment epithelium-derived factor (PEDF) blocks high glucose-induced inflammatory reactions in endothelial cells through its anti-oxidative properties. Int J Cardiol 2013; 168: 3004-3006
    CrossrefPubMedGoogle Scholar
  • 17 Yamagishi S, Matsui T, Nakamura K, Ueda S, Noda Y, Imaizumi T. Pigment epithelium-derived factor (PEDF): its potential therapeutic implication in diabetic vascular complications. Curr Drug Targets 2008; 9: 1025-1029
    CrossrefPubMedGoogle Scholar
  • 18 Ide Y, Matsui T, Ishibashi Y, Takeuchi M, Yamagishi S. Pigment epithelium-derived factor inhibits advanced glycation end product-elicited mesangial cell damage by NF-kappaB activation. Microvasc Res 2010; 80: 227-232
    CrossrefPubMedGoogle Scholar
  • 19 Maeda S, Matsui T, Takeuchi M, Yoshida Y, Yamakawa R, Fukami K, Yamagishi S. Pigment epithelium-derived factor (PEDF) inhibits proximal tubular cell injury in early diabetic nephropathy by suppressing advanced glycation end products (AGEs)-receptor (RAGE) axis. Pharmacol Res 2011; 63: 241-248
    CrossrefPubMedGoogle Scholar
  • 20 Wang JJ, Zhang SX, Mott R, Knapp RR, Cao W, Lau K, Ma JX. Salutary effect of pigment epithelium-derived factor in diabetic nephropathy: evidence for antifibrogenic activities. Diabetes 2006; 55: 1678-1685
    CrossrefPubMedGoogle Scholar
  • 21 Wang JJ, Zhang SX, Mott R, Chen Y, Knapp RR, Cao W, Ma JX. Anti-inflammatory effects of pigment epithelium-derived factor in diabetic nephropathy. Am J Physiol Renal Physiol 2008; 294: F1166-F1173
    CrossrefPubMedGoogle Scholar
  • 22 Kawaguchi T, Yamagishi S, Sata M. Structure-function relationships of PEDF. Curr Mol Med 2010; 10: 302-311
    CrossrefPubMedGoogle Scholar
  • 23 Matsui T, Nishino Y, Maeda S, Yamagishi S. PEDF-derived peptide inhibits corneal angiogenesis by suppressing VEGF expression. Microvasc Res 2012; 84: 105-108
    CrossrefPubMedGoogle Scholar
  • 24 Yamagishi S, Inagaki Y, Amano S, Okamoto T, Takeuchi M, Makita Z. Pigment epithelium-derived factor protects cultured retinal pericytes from advanced glycation end product-induced injury through its antioxidative properties. Biochem Biophys Res Commun 2002; 296: 877-882
    CrossrefPubMedGoogle Scholar
  • 25 Abe R, Yamagishi S, Fujita Y, Hoshina D, Sasaki M, Nakamura K, Matsui T, Shimizu T, Bucala R, Shimizu H. Topical application of anti-angiogenic peptides based on pigment epithelium-derived factor can improve psoriasis. J Dermatol Sci 2010; 57: 183-191
    CrossrefPubMedGoogle Scholar
  • 26 Bai L, Sheeley S, Sweedler JV. Analysis of Endogenous D-Amino Acid-Containing Peptides in Metazoa. Bioanal Rev 2009; 1: 7-24
    CrossrefPubMedGoogle Scholar
  • 27 Yamagishi S, Nakamura K, Matsui T, Inagaki Y, Takenaka K, Jinnouchi Y, Yoshida Y, Matsuura T, Narama I, Motomiya Y, Takeuchi M, Inoue H, Yoshimura A, Bucala R, Imaizumi T. Pigment epithelium-derived factor inhibits advanced glycation end product-induced retinal vascular hyperpermeability by blocking reactive oxygen species-mediated vascular endothelial growth factor expression. J Biol Chem 2006; 281: 20213-20220
    CrossrefPubMedGoogle Scholar
  • 28 Yoshida Y, Yamagishi S, Matsui T, Jinnouchi Y, Fukami K, Imaizumi T, Yamakawa R. Protective role of pigment epithelium-derived factor (PEDF) in early phase of experimental diabetic retinopathy. Diabetes Metab Res Rev 2009; 25: 678-686
    CrossrefPubMedGoogle Scholar
  • 29 Fujimura T, Yamagishi S, Ueda S, Fukami K, Shibata R, Matsumoto Y, Kaida Y, Hayashida A, Koike K, Matsui T, Nakamura K, Okuda S. Administration of pigment epithelium-derived factor (PEDF) reduces proteinuria by suppressing decreased nephrin and increased VEGF expression in the glomeruli of adriamycin-injected rats. Nephrol Dial Transplant 2009; 24: 1397-1406
    CrossrefPubMedGoogle Scholar
  • 30 Yamagishi S, Matsui T, Nakamura K, Takeuchi M, Imaizumi T. Pigment epithelium-derived factor (PEDF) prevents diabetes- or advanced glycation end products (AGE)-elicited retinal leukostasis. Microvasc Res 2006; 72: 86-90
    CrossrefPubMedGoogle Scholar
  • 31 Lee HB, Ha H. Plasminogen activator inhibitor-1 and diabetic nephropathy. Nephrology (Carlton) Suppl 2005; 10: S11-S13
    PubMedGoogle Scholar
  • 32 Collins SJ, Alexander SL, Lopez-Guisa JM, Cai X, Maruvada R, Chua SC, Zhang G, Okamura DM, Matsuo S, Eddy AA. Plasminogen activator inhibitor-1 deficiency has renal benefits but some adverse systemic consequences in diabetic mice. Nephron Exp Nephrol 2006; 104: e23-e34
    CrossrefPubMedGoogle Scholar
  • 33 Zhang J, Gu C, Lawrence DA, Cheung AK, Huang Y. A plasminogen activator inhibitor type 1 mutant retards diabetic nephropathy in db/db mice by protecting podocytes. Exp Physiol 2014; 99: 802-815
    CrossrefPubMedGoogle Scholar
  • 34 Ojima A, Matsui T, Nishino Y, Nakamura N, Yamagishi S. Empagliflozin, an Inhibitor of Sodium-Glucose Cotransporter 2 Exerts Anti-Inflammatory and Antifibrotic Effects on Experimental Diabetic Nephropathy Partly by Suppressing AGEs-Receptor Axis. Horm Metab Res 2015; 47: 686-692
    Article in Thieme ConnectPubMedGoogle Scholar
  • 35 Awad AS, Gao T, Gvritishvili A, You H, Liu Y, Cooper TK, Reeves WB, Tombran-Tink J. Protective role of small pigment epithelium-derived factor (PEDF) peptide in diabetic renal injury. Am J Physiol Renal Physiol 2013; 306: F891-F900
    PubMedGoogle Scholar