Glomerular overproduction of oxygen radicals in Mpv17 gene-inactivated mice causes podocyte foot process flattening and proteinuria: A model of steroid-resistant nephrosis sensitive to radical scavenger therapy.
Focal segmental glomerulosclerosis is a steroid-resistant glomerular disease characterized by foot process flattening and heavy proteinuria. A similar disease was found to occur spontaneously in mice in which the Mpv17 gene was inactivated by retroviral insertion (Mpv17-/- mice). Here evidence is provided that glomerular damage in this murine model is due to overproduction of oxygen radicals and accumulation of lipid peroxidation adducts that were found in isolated glomeruli of Mpv17-/- mice. The development of glomerular disease in Mpv17-/- mice was inhibited by scavengers of oxygen radicals (dithiomethylurea) and lipid peroxidation (probucol), but not by steroid treatment. Although the glomerular polyanion was greatly reduced in proteinuric Mpv17-/- mice, it was preserved by antioxidative therapy. These results indicate that the glomerular disease in Mpv17-/- mice qualifies as a model of steroid-resistant focal segmental glomerulosclerosis and that experimental therapies with scavengers of oxygen radicals and lipid peroxidation efficiently ameliorate glomerular damage.
Binder
C J
CJ
Department of Clinical Pathology, University of Vienna, Vienna, Austria.
Weiher
H
H
Exner
M
M
Kerjaschki
D
D
D000375:Aging; D000419:Albuminuria; D000818:Animals; D004195:Disease Models, Animal; D016166:Free Radical Scavengers / Q000627:therapeutic use; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005938:Glucocorticoids / Q000627:therapeutic use; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008054:Lipid Peroxides / Q000378:metabolism; D008565:Membrane Proteins; D008775:Methylprednisolone / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011341:Probucol / Q000627:therapeutic use; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D011507:Proteinuria / Q000175:diagnosis; D017382:Reactive Oxygen Species / Q000378:metabolism; D012795:Sialoglycoproteins / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D013890:Thiourea / Q000031:analogs & derivatives / Q000627:therapeutic use
D016166:Free Radical Scavengers; D005938:Glucocorticoids; D008054:Lipid Peroxides; D008565:Membrane Proteins; C065292:Mpv17 protein, mouse; D011506:Proteins; D017382:Reactive Oxygen Species; D012795:Sialoglycoproteins; C001643:podocalyxin; D013481:Superoxides; C038983:1,3-dimethylthiourea; D013890:Thiourea; D011341:Probucol; D008775:Methylprednisolone