Research Abstract |
In this study, we investigated the effect of inhibition of oxidative stress produced by podocytes in diabetic nephropathy. Podocytes express classic phagocytic NADPH oxidase and NADPH oxidase expression and superoxide production were increased in the streptozotocin-induced diabetic rats as well as in hypertensive rats. NADPH oxidase is regulated by angiotensin II, TNF-a and IL-1f3, and ACE inhibitor, ATI receptor blocker (ARB) as well as p38 MAPI( inhibitor suppressed the expression of NADPH oxidase, decreased renal radical production and ameliorated microalbuminuria. The suppression of platelet-derived cytokines by dipyridamole contributed to the suppression of NADPH oxidase and enhanced NOS expression to maintain microcirculation. The NADPH oxidase inhibitor, apocynin showed a stronger inhibition of radical production in the kidney than SOD and decreased proteinuria. As nephrin is located in the lipid raft of podocyte's membrane, a high cholesterol condition may have some influence in
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nephrin expression in the podocyte and its barrier function in proteinuria. Diabetic rat fed with a high cholesterol diet showed enhanced expression of NNDPH oxidase in podocytes as well as enhanced ICAM-1 expression in the glomerular endothelial cells with enhanced microphage migration. Gliclazide has been attributed an anti-oxidant effect due to its azabicyclo-octyl ring, this drug showed significant reduction of oxidative stress by suppression of renal NADPH oxidase and macrophage migration and consequently reduced proteinuria compared to glibenclamide that has no effect on radical reduction. Incubation of podocytes from isolated glomeruli with angiotensin II showed changes in NADPH oxidase expression and actin distribution, and these changes may regulate nephrin expression in podocytes, but we have not reached a conclusion yet. Microalbuininuria is not only regulated by poclocyte function but also by endocytosis of albumin in the proximal convoluted tubules via megalin. ACE inhibitor and ARB up-regulated megalin expression in proximal tubule and ameliorated endocytosis of albumin and reduced microalbuminuria in diabetic rat. In conclusion, reduction of NADPH oxidase expression in podocytes and its products using various interventions have an important role to reduce proteinuria in diabetic nephropathy. Less
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