| Budget Amount *help |
¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 2005: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000)
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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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