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

Sirt1 的肾脏特异性过度表达可预防慢性肾脏疾病。

基本信息

批准号：
22790800
负责人：
HASEGAWA Kazuhiro
金额：
$ 2.58万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2010
资助国家：
日本
起止时间：
2010 至 2011
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22790800/
关键词：
慢性腎臓病近位尿細管 Sirt1 腎臓内科学近立尿細管 SIRT1

项目摘要

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.

NAD依赖性脱乙酰基酶，SIRT1赋予各种组织中的保护作用。尽管据报道，卡路里限制或特定的SIRT1激活剂的全身SIRT1诱导会增加胰岛素的分泌或减轻胰岛素抵抗，但肾脏SIRT1在糖尿病性肾病中的作用尚未阐明。我们以前曾报道过，我们的TG小鼠对SIRT1的肾脏特异性过表达对AKI有保护（JBC 2010）。但是，肾脏SIRT1和CKD之间的相关性尚不清楚。在这里，我们探讨了肾脏SIRT1在糖尿病性肾病（DN）中的作用。 WT或TG小鼠通过用链唑霉素（STZ）治疗渲染DN。将八周大的雄性WT或SIRT1 TG小鼠接受腹膜内注射盐水（对照）或链霉菌素，持续5天（WT+SAL，WT+STZ，TG+SAL，TG+STZ）。 2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小鼠呈现出突出的蛋白尿，并带有足迹过程。 SIRT1表达在近端小管和足细胞中降低。在各个分子中，紧密的连接蛋白Claudin-1（一种顶层上皮细胞标记）在足细胞中被异位上调。相反，这些发现在TG+STZ中减弱。在与Claudin-1直接转染的足细胞中，狭缝隔膜蛋白，足霉素和突触蛋白的表达下调，白蛋白渗透率显着提高。在非DN态，SIRT1下调了Claudin-1表达。相反，在DN中，HG诱导的SIRT1下调增加了Claudin-1的表达，从而导致缝隙diaphragm蛋白的下调以及Podocytes的白蛋白渗透性的增加。这种新颖的机制有助于DN中的蛋白尿。