Lipid peroxidation in human proteinuric disease.
BACKGROUND
While metabolically generated oxidants are produced locally in experimental glomerular diseases, little is still known of their significance and the respective scavenger systems in human glomerular diseases.


METHODS
Here we studied kidneys from patients with congenital nephrotic syndrome of the Finnish type (CNF), a human model disease of isolated proteinuria. Expression of specific mRNAs for a major antioxidant system against lipoperoxidation [phospholipid hydroperoxide glutathione peroxidase (PHGPx)] and for mitochondrial proteins were studied in Northern blotting together with analysis of PHGPx in semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). The respective proteins and lipoperoxide (LPO) adducts malonyldialdehyde (MDA) and 4-hydroxynonenal (4-HNE) were analyzed in immunohistochemistry.


RESULTS
PHGPx and the mitochondrially encoded subunits of cytochrome-c-oxidase were distinctly down-regulated within the glomeruli of CNF kidneys. These changes were confirmed in semiquantitative RT-PCR. Increases of lipoperoxidation products MDA and 4-HNE were constantly found in the glomeruli of CNF. In agreement with findings in CNF, similar results were obtained in biopsies from other human glomerular diseases.


CONCLUSIONS
These findings suggest that local mitochondrial damage initiates LPO, which then causes deposition of the cytotoxic LPO products in glomeruli, as seen especially in CNF kidneys. Together with down-regulation of the local antioxidant protection, these may be important pathophysiologic mechanisms in human glomerular disease.
Solin
M L
ML
The Haartman Institute, Division of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland.
Ahola
H
H
Haltia
A
A
Ursini
F
F
Montine
T
T
Roveri
A
A
Kerjaschki
D
D
Holthöfer
H
H
D000293:Adolescent; D000447:Aldehydes / Q000378:metabolism; D015152:Blotting, Northern; D002648:Child; D002675:Child, Preschool; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008054:Lipid Peroxides / Q000378:metabolism*; D008315:Malondialdehyde / Q000378:metabolism; D009404:Nephrotic Syndrome / Q000151:congenital / Q000378:metabolism / Q000652:urine; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011507:Proteinuria / Q000209:etiology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000447:Aldehydes; D007527:Isoenzymes; D008054:Lipid Peroxides; D012333:RNA, Messenger; D008315:Malondialdehyde; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; D011451:Prostaglandin-Endoperoxide Synthases; C027576:4-hydroxy-2-nonenal