Selective albuminuria via podocyte albumin transport in puromycin nephrotic rats is attenuated by an inhibitor of NADPH oxidase

• Published in: Kidney international Vol. 80; no. 12; pp. 1328 - 1338
• Main Authors: Kinugasa, Satoshi, Tojo, Akihiro, Sakai, Tatsuo, Tsumura, Harukuni, Takahashi, Masafumi, Hirata, Yasunobu, Fujita, Toshiro
• Format: Journal Article
• Language: English
• Published: Basingstoke Elsevier Inc 01.12.2011; Nature Publishing Group; Elsevier Limited
• Subjects: Acetophenones - pharmacology; Albuminuria - chemically induced; Albuminuria - enzymology; Albuminuria - pathology; Albuminuria - prevention & control; Albuminuria - urine; Animals; Biological and medical sciences; Biological Transport; Disease Models, Animal; Endocytosis - drug effects; Enzyme Inhibitors - pharmacology; glomerular filtration barrier; Glomerulonephritis; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Histocompatibility Antigens Class I - metabolism; Humans; Immunohistochemistry; Immunoprecipitation; Kinetics; Male; Medical sciences; Microscopy, Confocal; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; NADPH oxidase; NADPH Oxidases - antagonists & inhibitors; NADPH Oxidases - metabolism; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Nephrosis, Lipoid - chemically induced; Nephrosis, Lipoid - drug therapy; Nephrosis, Lipoid - enzymology; Nephrosis, Lipoid - pathology; Nephrosis, Lipoid - urine; nephrotic syndrome; Oxidative Stress - drug effects; podocyte; Podocytes - drug effects; Podocytes - enzymology; Podocytes - ultrastructure; Puromycin; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Rats, Transgenic; reactive oxygen species; Reactive Oxygen Species - metabolism; Receptors, Fc - metabolism; Serum Albumin - metabolism; Urinary system involvement in other diseases. Miscellaneous; Urinary tract. Prostate gland; glomerular filtration barrier; NADPH oxidase; nephrotic syndrome; podocyte; reactive oxygen species; Glomerulonephritis; Antineoplastic agent; Oxidative stress; Reactive oxygen species; Nephrology; Glomerular filtration; Rat; Kidney; Free radical; Urology; NAD(P)H oxidase; Puromycin; Aminonucleoside; Kidney disease; Oxygen; Urinary system disease; Enzyme; Rodentia; Albumin; Nephrotic syndrome; Renal glomerulus; Podocyte; Vertebrata; Antibiotic; Mammalia; NADPH dehydrogenase (quinone); Urinary system; Animal; Parasiticide; Inhibitor; Oxidoreductases; Transport; Proteinuria
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1038/ki.2011.282

The mechanism of selective albuminuria in minimal change nephrotic syndrome, in which glomerular capillaries are diffusely covered by effaced podocyte foot processes with reduced slit diaphragms, is unknown. Podocyte injury is due, in part, to NADPH-induced oxidative stress. Here we studied mechanism of selective albuminuria in puromycin aminonucleoside (PAN) nephrotic rats, a model of minimal change nephrotic syndrome. In these rats, Evans Blue-labeled human albumin was taken up by podocytes and its urinary excretion markedly increased, with retained selectivity for albumin. Immunogold scanning electron micrographic images found increased human albumin in podocyte vesicles and on the apical membrane in nephrotic compared with control rats. Apocynin, an inhibitor of NADPH oxidase, decreased superoxide production in podocytes, and inhibited endocytosis and urinary albumin excretion. Real-time confocal microscopy found an initial delay in the appearance of Evans Blue-labeled human albumin in the tubular lumen, reflecting the time needed for transcellular transport. Immunoprecipitation analysis indicated that FcRn, a receptor for albumin transport, mediated podocyte albumin transport, and treatment with anti-FcRn antibody reduced proteinuria in these nephrotic rats. Thus, podocyte albumin transport was enhanced in PAN nephrotic rats by means of FcRn, which may explain the mechanism of selective proteinuria. This was blocked by apocynin, suggesting a new therapeutic approach.