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


CONCLUSIONS
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.
Fujimura
Toshiko
T
Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
Yamagishi
Sho-ichi
S
Ueda
Seiji
S
Fukami
Kei
K
Shibata
Ryo
R
Matsumoto
Yuriko
Y
Kaida
Yusuke
Y
Hayashida
Ayako
A
Koike
Kiyomi
K
Matsui
Takanori
T
Nakamura
Kei-ichiro
K
Okuda
Seiya
S
D000818:Animals; D004195:Disease Models, Animal; D004317:Doxorubicin; D005136:Eye Proteins / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007275:Injections, Intravenous; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000652:urine*; D016328:NF-kappa B / Q000378:metabolism; D009404:Nephrotic Syndrome / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D009414:Nerve Growth Factors / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011507:Proteinuria / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015843:Serpins / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D000099174:Pigment Epithelium-Derived Factor
D004317:Doxorubicin; D005136:Eye Proteins; D008565:Membrane Proteins; D016328:NF-kappa B; D009414:Nerve Growth Factors; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D015843:Serpins; D042461:Vascular Endothelial Growth Factor A; D000099174:Pigment Epithelium-Derived Factor; C113267:nephrin