Activation of inflammasomes in podocyte injury of mice on the high fat diet: Effects of ASC gene deletion and silencing.
Activation of inflammasomes in podocyte injury of mice on the high fat diet: Effects of ASC gene deletion and silencing.
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DOI：
10.1016/j.bbamcr.2014.01.033
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发表时间：
2014-05
影响因子：
5.1
通讯作者：
Li, Pin-Lan
中科院分区：
文献类型：
--
作者：
Boini, Krishna M.;Xia, Min;Abais, Justin M.;Li, Guangbi;Pitzer, Ashley L.;Gehr, Todd W. B.;Zhang, Yang;Li, Pin-Lan
炎性小体是一种细胞内炎症机制，已被报道参与多种慢性退行性疾病，如动脉粥样硬化、自身炎症性疾病和阿尔茨海默病。本研究假设与凋亡相关斑点样蛋白（ASC）相关的炎性小体的形成和激活是导致肥胖相关足细胞损伤和随之而来的肾小球硬化的重要启动机制。为了验证这一假设，将Asc基因敲除（Asc−/−）、野生型（Asc+/+）和肾内Asc shRNA转染的野生型（Asc shRNA）小鼠喂食高脂饮食（HFD）或正常饮食（ND） 12周，以产生肥胖和相关的肾小球损伤。Western blot和RT-PCR分析表明，与Asc+/+小鼠相比，Asc−/−小鼠肾组织中Asc表达缺失，或者Asc shRNA转染小鼠肾组织中Asc表达显著降低。共聚焦显微镜和共免疫沉淀分析显示，HFD增强了足细胞中与Asc相关的炎症小体的形成，Asc与nod样受体蛋白3 （Nalp3）共定位。在Asc - / -和局部Asc shrna转染的小鼠中未观察到这种炎性体复合物聚集。饲喂HFD的Asc - / -和Asc shrna转染小鼠的caspase-1活性、IL-1β生成和肾小球损伤指数（GDI）也显著降低。在HFD上转染Asc - / -和Asc shRNA的小鼠中，GDI的降低伴随着蛋白尿、白蛋白尿的减少，足突细胞的足突消失和足突细胞狭缝隔膜分子的丢失。总之，足细胞炎症小体的激活和形成在肥胖相关肾小球损伤的发展中具有重要意义。
Inflammasome, an intracellular inflammatory machinery, has been reported to be involved in a variety of chronic degenerative diseases such as atherosclerosis, autoinflammatory diseases and Alzheimer’s disease. The present study hypothesized that the formation and activation of inflammasomes associated with apoptosis associated speck-like protein (ASC) are an important initiating mechanism resulting in obesity-associated podocyte injury and consequent glomerular sclerosis. To test this hypothesis, Asc gene knockout (Asc−/−), wild type (Asc+/+) and intrarenal Asc shRNA-transfected wild type (Asc shRNA) mice were fed a high fat diet (HFD) or normal diet (ND) for 12 weeks to produce obesity and associated glomerular injury. Western blot and RT-PCR analyses demonstrated that renal tissue Asc expression was lacking in Asc−/− mice or substantially reduced in Asc shRNA transfected mice compared to Asc+/+ mice. Confocal microscopic and co-immunoprecipitation analysis showed that the HFD enhanced the formation of inflammasome associated with Asc in podocytes as shown by colocalization of Asc with Nod-like receptor protein 3 (Nalp3). This inflammasome complex aggregation was not observed in Asc−/− and local Asc shRNA-transfected mice. The caspase-1 activity, IL-1β production and glomerular damage index (GDI), were also significantly attenuated in Asc−/− and Asc shRNA-transfected mice fed the HFD. This decreased GDI in Asc−/− and Asc shRNA transfected mice on the HFD was accompanied by attenuated proteinuria, albuminuria, foot process effacement of podocytes and loss of podocyte slit diaphragm molecules. In conclusion, activation and formation of inflammasomes in podocytes are importantly implicated in the development of obesity-associated glomerular injury.
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DOI：
10.1161/hypertensionaha.110.154302
发表时间：
2011-02
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
De Miguel C;Lund H;Mattson DL
通讯作者：
Mattson DL
影响因子：
29.7
作者：
Davis BK;Wen H;Ting JP
通讯作者：
Ting JP
影响因子：
120.7
作者：
Hedley, AA;Ogden, CL;Flegal, KM
通讯作者：
Flegal, KM
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
8.7
作者：
Horvath GL;Schrum JE;De Nardo CM;Latz E
通讯作者：
Latz E