4-hydroxy-2-nonenal and Nephrotic-Syndrome

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.. 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.. 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.. 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.

Topics: Adolescent; Aldehydes; Blotting, Northern; Child; Child, Preschool; Glutathione Peroxidase; Humans; Immunohistochemistry; Isoenzymes; Kidney; Lipid Peroxides; Malondialdehyde; Nephrotic Syndrome; Phospholipid Hydroperoxide Glutathione Peroxidase; Prostaglandin-Endoperoxide Synthases; Proteinuria; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

1. Reactive oxygen species are involved in the pathogenesis of puromycin aminonucleoside (PAN) nephrosis and alpha-tocopherol is one of the major anti-oxidants in the body. 2. In the present study, we measured the levels of alpha-tocopherol by high-performance liquid chromatography in the plasma and in nine tissues of control and nephrotic rats obtained 10 days after either 0.9% saline solution or PAN injection, respectively. 3. In nephrotic rats, alpha-tocopherol levels increased four-fold in plasma; however, the molar ratio of alpha-tocopherol/ cholesterol remained unchanged, suggesting that the increase in alpha-tocopherol content was attributable to an increase in plasma lipid concentration. 4. In nephrotic rats, the alpha-tocopherol/cholesterol ratio increased 1.33-fold in adrenal glands and 1.34-fold in the testis, but remained unchanged in heart, spleen, liver, kidney lung, brain and muscle. 5. These data suggest that, in PAN nephrotic rats, there are alterations in the distribution of alpha-tocopherol and there is no deficiency of alpha-tocopherol in plasma or tissues.

Topics: Aldehydes; Animals; Lipid Peroxidation; Male; Malondialdehyde; Nephrosis; Nephrotic Syndrome; Proteinuria; Puromycin Aminonucleoside; Rats; Rats, Wistar; Time Factors; Tissue Distribution; Vitamin E