Skip to main content

Advertisement

Log in

Expression of pigment-epithelium-derived factor during kidney development and aging

  • Regular Article
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Inhibitors and stimulators of endothelial cell growth are essential for the coordination of blood vessel formation during organ growth and development. In the adult kidney, one of the major inhibitors of angiogenesis is pigment-epithelium-derived factor (PEDF). We have analyzed the expression and distribution of PEDF during various stages of renal development and aging with particular emphasis on the formation of functional glomeruli. We show that PEDF gene expression and protein levels in the kidney significantly increase with age. We have detected PEDF in the mesenchyme and endothelial cells at all developmental stages studied, in all regions of the nephrogenic zone in which the formation of new blood vessels is associated with the development of nephrons and collecting ducts, and in mature podocytes in the adult kidney. Our results are the first to suggest that PEDF is important in early renal postnatal development, that it could be relevant to the maturation of glomerular function and the filtration barrier formed by these cells, and that it may serve as an anti-angiogenic modulator during kidney development.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Scheme 1
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Abramson LP, Stellmach V, Doll JA, Cornwell M, Arensman RM, Crawford SE (2003) Wilms’ tumor growth is suppressed by antiangiogenic pigment epithelium-derived factor in a xenograft model. J Pediatr Surg 38:336–342

    Article  PubMed  Google Scholar 

  • Alberdi E, Hyde CC, Becerra SP (1998) Pigment epithelium-derived factor (PEDF) binds to glycosaminoglycans: analysis of the binding site. Biochemistry 37:10643–10652

    Article  PubMed  CAS  Google Scholar 

  • Auricchio A, Behling KC, Maguire AM, O’Connor EM, Bennett J, Wilson JM, Tolentino MJ (2002) Inhibition of retinal neovascularization by intraocular viral-mediated delivery of anti-angiogenic agents. Mol Ther 6:490–494

    Article  PubMed  CAS  Google Scholar 

  • Behling KC, Surace EM, Bennett J (2002) Pigment epithelium-derived factor expression in the developing mouse eye. Mol Vis 8:449–454

    PubMed  CAS  Google Scholar 

  • Cai J, Jiang WG, Grant MB, Boulton M (2006) Pigment epithelium-derived factor inhibits angiogenesis via regulated intracellular proteolysis of vascular endothelial growth factor receptor 1. J Biol Chem 281:3604–3613

    Article  PubMed  CAS  Google Scholar 

  • Cheng HT, Kopan R (2005) The role of Notch signaling in specification of podocyte and proximal tubules within the developing mouse kidney. Kidney Int 68:1951–1952

    Article  PubMed  CAS  Google Scholar 

  • Crawford SE, Stellmach V, Ranalli M, Huang X, Huang L, Volpert O, De Vries GH, Abramson LP, Bouck N (2001) Pigment epithelium-derived factor (PEDF) in neuroblastoma: a multifunctional mediator of Schwann cell antitumor activity. J Cell Sci 114:4421–4428

    PubMed  CAS  Google Scholar 

  • Darland DC, D’Amore PA (2001) Cell-cell interactions in vascular development. Curr Top Dev Biol 52:107–149

    Article  PubMed  CAS  Google Scholar 

  • Dawson DW, Volpert OV, Gillis P, Crawford SE, Xu H, Benedict W, Bouck NP (1999) Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science 285:245–248

    Article  PubMed  CAS  Google Scholar 

  • Doll JA, Stellmach VM, Bouck NP, Bergh AR, Lee C, Abramson LP, Cornwell ML, Pins MR, Borensztajn J, Crawford SE (2003) Pigment epithelium-derived factor regulates the vasculature and mass of the prostate and pancreas. Nat Med 9:774–780

    Article  PubMed  CAS  Google Scholar 

  • Eremina V, Quaggin SE (2004) The role of VEGF-A in glomerular development and function. Curr Opin Nephrol Hypertens 13:9–15

    Article  PubMed  CAS  Google Scholar 

  • Eremina V, Sood M, Haigh J, Nagy A, Lajoie G, Ferrara N, Gerber HP, Kikkawa Y, Miner JH, Quaggin SE (2003) Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest 111:707–716

    Article  PubMed  CAS  Google Scholar 

  • Gehlbach P, Demetriades AM, Yamamoto S, Deering T, Duh EJ, Yang HS, Cingolani C, Lai H, Wei L, Campochiaro PA (2003) Periocular injection of an adenoviral vector encoding pigment epithelium-derived factor inhibits choroidal neovascularization. Gene Ther 10:637–646

    Article  PubMed  CAS  Google Scholar 

  • Gomez RA, Norwood VF, Tufro-McReddie A (1997) Development of the kidney vasculature. Microsc Res Tech 39:254–260

    Article  PubMed  CAS  Google Scholar 

  • Griffin SV, Petermann AT, Durvasula RV, Shankland SJ (2003) Podocyte proliferation and differentiation in glomerular disease: role of cell-cycle regulatory proteins. Nephrol Dial Transplant 18 (Suppl 6):vi8–vi13

    PubMed  CAS  Google Scholar 

  • Guan M, Pang CP, Yam HF, Cheung KF, Liu WW, Lu Y (2004) Inhibition of glioma invasion by overexpression of pigment epithelium-derived factor. Cancer Gene Ther 11:325–332

    Article  PubMed  CAS  Google Scholar 

  • Hjelmeland LM, Cristofolo VJ, Funk W, Rakoczy E, Katz ML (1999) Senescence of the retinal pigment epithelium. Mol Vis 5:33

    PubMed  CAS  Google Scholar 

  • Jablonski MM, Tombran-Tink J, Mrazek DA, Iannaccone A (2000) Pigment epithelium-derived factor supports normal development of photoreceptor neurons and opsin expression after retinal pigment epithelium removal. J Neurosci 20:7149–7157

    PubMed  CAS  Google Scholar 

  • Kitamoto Y, Tokunaga H, Tomita K (1997) Vascular endothelial growth factor is an essential molecule for mouse kidney development: glomerulogenesis and nephrogenesis. J Clin Invest 99:2351–2357

    Article  PubMed  CAS  Google Scholar 

  • Kitamoto Y, Tokunaga H, Miyamoto K, Tomita K (2002) VEGF is an essential molecule for glomerular structuring. Nephrol Dial Transplant 17 (Suppl 9):25–27

    Article  PubMed  CAS  Google Scholar 

  • Kloth S, Ebenbeck C, Monzer J, Vries U de, Minuth WW (1997) Three-dimensional organization of the developing vasculature of the kidney. Cell Tissue Res 287:193–201

    Article  PubMed  CAS  Google Scholar 

  • Kloth S, Gerdes J, Wanke C, Minuth WW (1998) Basic fibroblast growth factor is a morphogenic modulator in kidney vessel development. Kidney Int 53:970–978

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi N, Kriz W (2002) Introduction to the podocyte issue: more than eight enigmas. Microsc Res Tech 57:187–188

    Article  PubMed  Google Scholar 

  • Kobayashi N, Gao SY, Chen J, Saito K, Miyawaki K, Li CY, Pan L, Saito S, Terashita T, Matsuda S (2004) Process formation of the renal glomerular podocyte: is there common molecular machinery for processes of podocytes and neurons? Anat Sci Int 79:1–10

    Article  PubMed  CAS  Google Scholar 

  • Kriz W, Hosser H, Hahnel B, Gretz N, Provoost AP (1998) From segmental glomerulosclerosis to total nephron degeneration and interstitial fibrosis: a histopathological study in rat models and human glomerulopathies. Nephrol Dial Transplant 13:2781–2798

    Article  PubMed  CAS  Google Scholar 

  • Liu H, Ren JG, Cooper WL, Hawkins CE, Cowan MR, Tong PY (2004) Identification of the antivasopermeability effect of pigment epithelium-derived factor and its active site. Proc Natl Acad Sci USA 101:6605–6610

    Article  PubMed  CAS  Google Scholar 

  • Matsumoto K, Ishikawa H, Nishimura D, Hamasaki K, Nakao K, Eguchi K (2004) Antiangiogenic property of pigment epithelium-derived factor in hepatocellular carcinoma. Hepatology 40:252–259

    Article  PubMed  CAS  Google Scholar 

  • McCright B (2003) Notch signaling in kidney development. Curr Opin Nephrol Hypertens 12:5–10

    Article  PubMed  CAS  Google Scholar 

  • Mori K, Duh E, Gehlbach P, Ando A, Takahashi K, Pearlman J, Mori K, Yang HS, Zack DJ, Ettyreddy D, Brough DE, Wei LL, Campochiaro PA (2001) Pigment epithelium-derived factor inhibits retinal and choroidal neovascularization. J Cell Physiol 188:253–263

    Article  PubMed  CAS  Google Scholar 

  • Mori K, Gehlbach P, Ando A, McVey D, Wei L, Campochiaro PA (2002a) Regression of ocular neovascularization in response to increased expression of pigment epithelium-derived factor. Invest Ophthalmol Vis Sci 43:2428–2434

    Google Scholar 

  • Mori K, Gehlbach P, Yamamoto S, Duh E, Zack DJ, Li Q, Berns KI, Raisler BJ, Hauswirth WW, Campochiaro PA (2002b) AAV-mediated gene transfer of pigment epithelium-derived factor inhibits choroidal neovascularization. Invest Ophthalmol Vis Sci 43:1994–2000

    Google Scholar 

  • Petersen SV, Valnickova Z, Enghild JJ (2003) Pigment-epithelium-derived factor (PEDF) occurs at a physiologically relevant concentration in human blood: purification and characterization. Biochem J 374:199–206

    Article  PubMed  CAS  Google Scholar 

  • Pignolo RJ, Francis MK, Rotenberg MO, Cristofalo VJ (2003) Putative role for EPC-1/PEDF in the G0 growth arrest of human diploid fibroblasts. J Cell Physiol 195:12–20

    Article  PubMed  CAS  Google Scholar 

  • Quan GM, Ojaimi J, Li Y, Kartsogiannis V, Zhou H, Choong PF (2005) Localization of pigment epithelium-derived factor in growing mouse bone. Calcif Tissue Int 76:146–153

    Article  PubMed  CAS  Google Scholar 

  • Risau W (1997) Mechanisms of angiogenesis. Nature 386:671–674

    Article  PubMed  CAS  Google Scholar 

  • Sage H (1997) Pieces of eight: bioactive fragments of extracellular proteins as regulators of angiogenesis. Trends Cell Biol 7:182–186

    Article  CAS  Google Scholar 

  • Sariola H, Saarma M, Sainio K, Arumae U, Palgi J, Vaahtokari A, Thesleff I, Karavanov A (1991) Dependence of kidney morphogenesis on the expression of nerve growth factor receptor. Science 254:571–573

    Article  PubMed  CAS  Google Scholar 

  • Sawant S, Aparicio S, Tink AR, Lara N, Barnstable CJ, Tombran-Tink J (2004) Regulation of factors controlling angiogenesis in liver development: a role for PEDF in the formation and maintenance of normal vasculature. Biochem Biophys Res Commun 325:408–413

    Article  PubMed  CAS  Google Scholar 

  • Saxen L, Sariola H (1987) Early organogenesis of the kidney. Pediatr Nephrol 1:385–392

    Article  PubMed  CAS  Google Scholar 

  • Stellmach V, Crawford SE, Zhou W, Bouck N (2001) Prevention of ischemia-induced retinopathy by the natural ocular antiangiogenic agent pigment epithelium-derived factor. Proc Natl Acad Sci USA 98:2593–2597

    Article  PubMed  CAS  Google Scholar 

  • Takenaka K, Yamagishi S, Jinnouchi Y, Nakamura K, Matsui T, Imaizumi T (2005) Pigment epithelium-derived factor (PEDF)-induced apoptosis and inhibition of vascular endothelial growth factor (VEGF) expression in MG63 human osteosarcoma cells. Life Sci 77:3231–3241

    Article  PubMed  CAS  Google Scholar 

  • Tombran-Tink J, Barnstable CJ (2003) Therapeutic prospects for PEDF: more than a promising angiogenesis inhibitor. Trends Mol Med 9:244–250

    Article  PubMed  CAS  Google Scholar 

  • Tombran-Tink J, Barnstable CJ (2004) Osteoblasts and osteoclasts express PEDF, VEGF-A isoforms, and VEGF receptors: possible mediators of angiogenesis and matrix remodeling in the bone. Biochem Biophys Res Commun 316:573–579

    Article  PubMed  CAS  Google Scholar 

  • Tombran Tink J, Chader GG, Johnson LV (1991) PEDF: a pigment epithelium derived factor with potent neuronal differentiative activity. Exp Eye Res 53:411–414

    Article  PubMed  CAS  Google Scholar 

  • Tombran-Tink J, Mazuruk K, Rodriguez IR, Chung D, Linker T, Englander E, Chader GJ (1996) Organization, evolutionary conservation, expression and unusual Alu density of the human gene for pigment epithelium-derived factor, a unique neurotrophic serpin. Mol Vis 2:11

    PubMed  CAS  Google Scholar 

  • Uehara H, Miyamoto M, Kato K, Ebihara Y, Kaneko H, Hashimoto H, Murakami Y, Hase R, Takahashi R, Mega S, Shichinohe T, Kawarada Y, Itoh T, Okushiba S, Kondo S, Katoh H (2004) Expression of pigment epithelium-derived factor decreases liver metastasis and correlates with favorable prognosis for patients with ductal pancreatic adenocarcinoma. Cancer Res 64:3533–3537

    Article  PubMed  CAS  Google Scholar 

  • Wang JJ, Zhang SX, Lu K, Chen Y, Mott R, Sato S, Ma JX (2005) Decreased expression of pigment epithelium-derived factor is involved in the pathogenesis of diabetic nephropathy. Diabetes 54:243–250

    Article  PubMed  CAS  Google Scholar 

  • Wong WT, Rex TS, Auricchio A, Maguire AM, Chung D, Tang W, Bennett J (2004) Effect of over-expression of pigment epithelium derived factor (PEDF) on developing retinal vasculature in the mouse. Mol Vis 10:837–844

    PubMed  CAS  Google Scholar 

  • Yamagishi SI, Adachi H, Abe A, Yashiro T, Enomoto M, Furuki K, Hino A, Jinnouchi Y, Takenaka K, Matsui T, Nakamura K, Imaizumi T (2006) Elevated serum levels of pigment epithelium-derived factor (PEDF) in the metabolic syndrome. J Clin Endocrinol Metab (in press)

  • Yasui N, Mori T, Morito D, Matsushita O, Kourai H, Nagata K, Koide T (2003) Dual-site recognition of different extracellular matrix components by anti-angiogenic/neurotrophic serpin, PEDF. Biochemistry 42:3160–3167

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Prof. Dr. Ralph Witzgall, Institute for Molecular and Cellular Anatomy, University of Regensburg, for helpful comments and technical support, and Mrs. Eva-Maria Stoerr for technical assistance.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ana Luisa Pina.

Additional information

Ana Luisa Pina and Marion Kubitza contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pina, A.L., Kubitza, M., Brawanski, A. et al. Expression of pigment-epithelium-derived factor during kidney development and aging. Cell Tissue Res 329, 329–338 (2007). https://doi.org/10.1007/s00441-007-0420-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-007-0420-8

Keywords

Navigation