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NDT Advance Access published online on November 28, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn659
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Administration of pigment epithelium-derived factor (PEDF) reduces proteinuria by suppressing decreased nephrin and increased VEGF expression in the glomeruli of adriamycin-injected rats

Toshiko Fujimura1, Sho-ichi Yamagishi2, Seiji Ueda1, Kei Fukami1, Ryo Shibata1, Yuriko Matsumoto1, Yusuke Kaida1, Ayako Hayashida1, Kiyomi Koike1, Takanori Matsui2, Kei-ichiro Nakamura3 and Seiya Okuda1

1 Division of Nephrology, Department of Medicine 2 Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications 3 Division of Microscopic & Developmental Anatomy, Department of Anatomy, Kurume University School of Medicine, Kurume, Japan

Correspondence and offprint requests to: Sho-ichi Yamagishi, Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan. Tel: +81-942-31-7580; Fax: +81-942-31-7707; E-mail: shoichi{at}med.kurume-u.ac.jp



  Abstract

Background. Pigment epithelium-derived factor (PEDF) is a glycoprotein with potent neuronal differentiating activity. We, along with others, have recently found that PEDF inhibits retinal hyperpermeability by counteracting the biological effects of vascular endothelial growth factor (VEGF). However, the protective role of PEDF against nephrotic syndrome (NS), a condition of hyperpermeability in the glomerular capillaries, remains to be elucidated. In this study, we investigated whether and how PEDF reduced proteinuria in rats with adriamycin (ADR)-induced nephropathy (ADN), an experimental model of NS.

Methods. ADN was induced by a single intravenous injection of doxorubicin hydrochloride (n = 12). Half the ADN rats were intravenously administrated human recombinant PEDF; the other half were given vehicle everyday for up to 14 days. Control rats (n = 6) received vehicle only.

Results. In ADN, expression levels of PEDF in isolated glomeruli were significantly decreased, which were associated with a marked proteinuria and increased urinary excretion of nephrin, an index of podocyte damage. Loss of nephrin and decreased podocyte cell number and fusion of foot processes of podocytes with nuclear factor-kappa B (NF-{kappa}B) activation and VEGF overexpression were also observed in the glomeruli of rats with ADN. Intravenous administration of PEDF ameliorated all of these changes in ADN rats.

Conclusion. The present findings suggest that PEDF could reduce proteinuria by suppressing podocyte damage and decreased nephrin as well as increased VEGF expression in the glomeruli of ADN rats. Pharmacological up-regulation or substitution of PEDF may offer a promising therapeutic strategy for the treatment of nephrotic syndrome.

Keywords: hyperpermeability; nephrin; nephrotic syndrome; PEDF; VEGF

Received for publication: 7. 2.08
Accepted in revised form: 3.11.08


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