| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2011: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2010: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Research Abstract |
NAD-dependent deacetylase, Sirt1 confers protective effects in various tissues. Although it has been reported that whole body Sirt1 induction by calorie restriction or specific Sirt1 activators increases insulin secretion or attenuates insulin resistance, the role of kidney Sirt1 in diabetic nephropathy has not been elucidated. We previously reported that our Tg mice with kidney-specific overexpression of Sirt1 protected against AKI(JBC 2010). However, a correlation between renal Sirt1 and CKD is unclear. Here, we explore the role of renal Sirt1 in diabetic nephropathy(DN). WT or Tg mice were rendered DN by the treatment with streptozotocin(STZ). Eight weeks old male WT or Sirt1 Tg mice were subjected to intraperitoneal injection of saline(control) or streptozotocin with 50mg/kg/day for 5 days(WT+Sal, WT+STZ, Tg+Sal, Tg+STZ). After 2 or 6 months, we measured various blood and urine parameters, and kidney histology. WT+STZ mice were presented with prominent albuminuria with podocytes foot process effacement. Sirt1 expression was decreased in proximal tubules as well as podocotyes. Among various molecules, tight junction protein claudin-1, a parietal epithelial cell marker, was ectopically upregulated in podocytes. Conversely, these findings were attenuated in Tg+STZ. In podocytes with the direct transfection of claudin-1, the expressions of slit diaphragm proteins, podocin and synaptopodin were downregulated and albumin permeability was significantly increased. In non-DN state, Sirt1 downregulated claudin-1 expression. Oppositely, in DN, HG-induced Sirt1 downregulation increased the claudin-1 expression leading to the downregulation of slit diaphragm proteins and to the increase in podocytes' albumin permeability. This novel mechanism contributes to albuminuria in DN.
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