Adenovirus-mediated gene transfer and lipoprotein-mediated protein delivery of plasma PAF-AH ameliorates proteinuria in rat model of glomerulosclerosis.
Oxidative stress has been proposed to play a crucial role in glomerulosclerosis, although its in vivo demonstration has proved taxing given the difficulty of inducing gene expression in specific renal cells. In this study, we examined whether the liver-directed expression of plasma platelet-activating factor acetylhydrolase (PAF-AH) would affect the glomerular pathophysiology in Imai rats, an animal model for glomerulosclerosis. Adenovirus-mediated liver-directed gene delivery of human PAF-AH resulted in a significant increase in plasma PAF-AH activity, which was detected almost exclusively on HDL. Histological examination of rats overexpressing PAF-AH showed not only the deposition of PAF-AH in mesangial cells, but also a reduction in hydroxynonenal and matrix protein content in the glomeruli. In situ hybridization analysis was negative for human PAF-AH mRNA in the kidney, while injection of HDL abundant in PAF-AH resulted in the deposition of PAF-AH in mesangial cells. Urine protein levels did not increase in rats overexpressing PAF-AH, while those of control rats increased significantly with age. This study provides direct evidence of the in vivo role of an enzyme that degrades lipid peroxides during the progression of glomerulosclerosis. Adenovirus-mediated extrarenal gene expression and lipoprotein-mediated glomeruli-targeted protein delivery promise to be a novel therapeutic approach to glomerulosclerosis.
Iso-O
Naoyuki
N
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Noto
Hiroshi
H
Hara
Masumi
M
Togo
Masako
M
Karasawa
Ken
K
Ohashi
Noriko
N
Noiri
Eisei
E
Hashimoto
Yoshiaki
Y
Kadowaki
Takashi
T
Kimura
Satoshi
S
Watanabe
Tsuyoshi
T
Tsukamoto
Kazuhisa
K
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D003404:Creatinine / Q000097:blood; D015237:Dinoprost / Q000031:analogs & derivatives / Q000097:blood; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D005923:Glomerulosclerosis, Focal Segmental / Q000378:metabolism / Q000628:therapy*; D017403:In Situ Hybridization; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology; D008054:Lipid Peroxides / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000097:blood / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D050527:Mesangial Cells / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D011507:Proteinuria / Q000378:metabolism / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley
C115626:8,12-iso-isoprostane F2alpha-VI; D008054:Lipid Peroxides; D008075:Lipoproteins, HDL; D003404:Creatinine; D015237:Dinoprost; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase