2005 Fiscal Year Final Research Report Summary
A new mechanism of proteinuria : glomerular basement membrane shunt produced by oxidative stress
| Project/Area Number |
16590780
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Kidney internal medicine
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| Research Institution | The University of Tokyo |
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Principal Investigator |
TOJO Akihiro The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (50292917)
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| Project Period (FY) |
2004 – 2005
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| Keywords | proteinuria / glomerular basement membrane / oxidative stress / NADPH oxidase / diabetic nephropathy / nitric oxide / superoxide |
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| Research Abstract |
We investigated role of oxidative stress via NADPH oxidase on proteinuria. Oxidative stress plays an important role in the development of proteinuria and renal damage in diabetes and hypertension. The major source of oxidative stress is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived superoxide anion (O_2^<.->) that directly damage cell and also activate signaling of cell proliferation, adhesion molecules, and fibrosis. O_2^<.-> also inactivates endothelium derived nitric oxide and cause endothelial nitric oxide synthase uncoupling. Apocynin inhibits translocation of cytosolic components p47phox to the membrane components forming molecular cluster for massive production of superoxide. Apocynin reduced microalbuminuria in diabetic nephropathy with reduction of renal oxidative stress and increasing NO bioavailability (Kidney Int 67, 2005). Hypercholesterolemia additively increases oxidative stress in diabetes, as well as increases the adhesion molecule ICAM-1 and glom
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erular macrophage infiltration. Gliclazide has a special activity to scavenge superoxide with azabiocyclo-octyl-ring structure and reduced oxidative stress and proteinuria increasing NO bioavailability (Kidney Int65, 2004). In the spontaneously hypertensive rat and Dahl salt sensitive hypertensive rat with heart failure and in the streptozotocin-induced diabetic rats NADPH oxidase is increased via increased renal angiotensin II (AngII), and angiotensin converting enzyme inhibitor (ACEI) or AngII AT_1 receptor blocker (ARB) confer renal protection by decrease in NADPH oxidase expression (Curr Hypertens rev 1, 2005). The inhibitor of p38 MAPK suppresses IL-1β and TNF-α as well as ACE and renal angiotensin II, thus, p38 MAPK inhibitor decreases NADPH oxidase expression in the kidney and reduced proteinuria (J Hypertens 23, 2005). Electron microscopic observation showed NADPH oxidase expressed in the membrane of podocytes and produced superoxide on the cytoplasm membrane of podocytes and glomerular basement membrane (GBM) observed by CsCl_3 causing GBM damage. Infiltrating macrophage and neutrophil attached on the GBM also produce oxidative stress and generate GBM shunts or GBM ruptures. These GBM shunts or ruptures are also observed in the human renal biopsy specimens, however, they are not related to the amount of proteinuria and the degree of glomerular and interstitial damage. In summary, stimulation of NADPH oxidase in the podocytes has an important pathogenic role in the proteinuria with GBM damages including BGM shunts or ruptures in hypertension and diabetes, and suppression of renal NADPH oxidase is a promising strategy against renal damage. Less
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[Journal Article] Eplerenone shows renoprotective effect by reducing LOX-1 mediated adhesion molecule, PKC ε-MAPK-p90RSK, and Rho-kinase pathway.2005
Author(s)
Kobayashi N, Hara K, Tojo A, Onozato ML, Honda T, Yoshida K, Mita S, Tsubokou Y, Matsuoka H
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Journal Title
Hypertension 45
Pages: 538-544
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Non-sulfated form of the HNK-1 carbohydrate is expressed in mouse kidney.2005
Author(s)
Tagawa H, Kizuka Y, Ikeda T, Itoh S, Kawasaki N, Kurihara H, Onozato ML, Tojo A, Sakai T, Kawasaki T, Oka S
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Journal Title
J Biol Chem 280(25)
Pages: 23876-23883
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Non-sulfated form of the HNK-1 carbohydrate is expressed in mouse kidney.2005
Author(s)
Tagawa H, Kizuka Y, Ikeda T, Itoh S, Kawasaki N, Kurihara H, Onozato ML, Tojo A, Sakai T, Kawasaki T, Oka S.
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Journal Title
J Biol Chem 280(25)
Pages: 23876-23883
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Interactions of human organic anion transporters with diuretics.2004
Author(s)
Hasannejad H, Takeda M, Taki K, Jung SH, Babu E, Jutabha P, Khamdang S, Aleboyeh M, Onozato ML, Tojo A, Enomoto A, Anzai N, Narikawa S, Huang XL, Niwa T, Endou H
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Journal Title
J Pharmacol Exp Ther 65
Pages: 951-960
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Human organic cation transporter 3 mediates the transport of antiarrhythmic drugs.2004
Author(s)
Hasannejad H, Takeda M, Narikawa S, Huang XL, Enomoto A, Taki K, Niwa T, Jung SH, Onozato ML, Tojo A, Endou H
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Journal Title
Eur J Pharmcol 499
Pages: 45-51
Description
「研究成果報告書概要(和文)」より
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