Kidney-specific overexpression of Sirt1 protects against chronic kidney disease.

nad依赖性去乙酰化酶Sirt1在多种组织中具有保护作用。尽管有报道称，通过热量限制或特异性Sirt1激活剂诱导全身Sirt1可增加胰岛素分泌或减轻胰岛素抵抗，但肾脏Sirt1在糖尿病肾病中的作用尚未阐明。我们之前报道过Sirt1肾特异性过表达的Tg小鼠可预防AKI（JBC 2010）。然而，肾脏Sirt1与CKD之间的相关性尚不清楚。在这里，我们探讨肾脏Sirt1在糖尿病肾病（DN）中的作用。WT或Tg小鼠经链脲佐菌素（STZ）处理致DN。8周龄雄性WT或Sirt1 Tg小鼠腹腔注射生理盐水（对照）或链脲佐菌素（50mg/kg/天），连续5天（WT+Sal, WT+STZ, Tg+Sal, Tg+STZ）。2个月或6个月后，我们测量了各种血液和尿液参数以及肾脏组织学。WT+STZ小鼠出现明显的蛋白尿，足细胞足突消失。Sirt1在近端小管和足突细胞中的表达降低。在各种分子中，壁上皮细胞标记物紧密连接蛋白claudin-1在足细胞中异位上调。相反，这些发现在Tg+STZ中减弱。直接转染claudin-1后，足细胞中slit膈蛋白、podocin和synaptopodin的表达下调，白蛋白通透性显著增加。在非dn状态下，Sirt1下调claudin-1的表达。相反，在DN中，hg诱导的Sirt1下调增加了claudin-1的表达，导致slit膈蛋白下调，足细胞白蛋白通透性增加。这种新机制有助于DN患者蛋白尿。

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.