Protection of alpha(3) integrin-mediated podocyte shape by superoxide dismutase in the puromycin aminonucleoside nephrosis rat.
Because reactive oxygen species (ROS) are involved in the development of puromycin aminonucleoside nephrosis (PAN), we examined whether superoxide dismutase (SOD) could ameliorate this condition. Phosphatidyl choline-bound SOD (PC-SOD) has higher affinity for the cell membrane than recombinant human SOD (rhSOD). In this study, PC-SOD had a longer half-life in the circulation and also higher affinity to renal fractions (glomerulus, brush border, and tubulus) than rhSOD. PAN was induced in rats with single injections of puromycin aminonucleoside. Rats were divided into four groups: group P, PAN rats without treatment; group PC-T and group rh-T, PAN rats treated with 30,000 U/kg PC-SOD and rhSOD, respectively; and group C, normal controls. The effect of PC-SOD versus rhSOD on PAN was evaluated by morphological podocyte changes (podocyte density along the GBM) and alpha(3) integrin expression at days 4 and 10. Proteinuria was measured over time until day 14. Distribution and quantitation of alpha(3) integrin were studied by confocal laser scan microscopy. On day 4, glomerular ROS was measured by chemiluminescence without stimulation. PC-SOD decreased proteinuria to the control level, but rhSOD only decreased proteinuria by 31%. PC-SOD significantly improved podocyte density (P < 0.05 versus group P). Total alpha(3) integrin expression decreased in the P and rh-T groups at day 4 and then had recovered by day 10, but the polarity of the site of expression did not recover. PC-T preserved both the amount and polarity of integrin expression on days 4 and 10. PC-SOD significantly suppressed ROS generation in PAN (P < 0.05). These findings suggest that alpha(3) integrin regulates glomerular permeability by maintaining podocyte shape and adhesion, which is disrupted by ROS overproduction.
Kojima
K
K
Department of Internal Medicine, Teikyo University School of Medicine, Kaga, Itabashi-ku, Tokyo, Japan. kojima@med.teikyo-u.ac.jp
Matsui
K
K
Nagase
M
M
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects; D015703:Antigens, CD / Q000187:drug effects* / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002452:Cell Count / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D016166:Free Radical Scavengers / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use*; D006207:Half-Life; D006801:Humans; D039422:Integrin alpha3; D016023:Integrins / Q000187:drug effects* / Q000378:metabolism; D007678:Kidney Glomerulus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism; D008163:Luminescent Measurements; D008297:Male; D018613:Microscopy, Confocal; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism; D009401:Nephrosis / Q000188:drug therapy*; D010713:Phosphatidylcholines / Q000378:metabolism; D020011:Protective Agents / Q000378:metabolism / Q000627:therapeutic use*; D011507:Proteinuria / Q000517:prevention & control / Q000652:urine; D011692:Puromycin Aminonucleoside / Q000009:adverse effects; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins; D013482:Superoxide Dismutase / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use*
D000903:Antibiotics, Antineoplastic; D015703:Antigens, CD; D016166:Free Radical Scavengers; D039422:Integrin alpha3; D016023:Integrins; D010713:Phosphatidylcholines; D020011:Protective Agents; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D011692:Puromycin Aminonucleoside; D013482:Superoxide Dismutase