Instigation of NLRP3 inflammasome activation and glomerular injury in mice on the high fat diet: role of acid sphingomyelinase gene.
Instigation of NLRP3 inflammasome activation and glomerular injury in mice on the high fat diet: role of acid sphingomyelinase gene.
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DOI：
10.18632/oncotarget.8023
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发表时间：
2016-04-05
期刊：
影响因子：
--
通讯作者：
Li PL
中科院分区：
文献类型：
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作者：
Boini KM;Xia M;Koka S;Gehr TW;Li PL
据报道，神经酰胺在肥胖症和不同的病理条件下启动炎性小体的形成和激活。本研究旨在探讨酸性鞘磷脂酶（Asm）在高脂饮食（HFD）诱导的炎性小体形成、活化及肾小球损伤中的作用。Asm基因敲除（Asm-/-）和野生型（Asm+/+）小鼠（有或没有Asm短发夹RNA（shRNA）转染）喂食HFD或正常食物12周，以产生肥胖和相关的肾小球损伤。HFD显著增强Asm+/+小鼠肾小球中Asm活性、神经酰胺产生、Nlrp 3（Nod样受体蛋白3）与ASC（肾小球疾病相关斑点样蛋白）或Caspase-1的共定位、NADPH依赖性超氧化物（O2·−）产生。然而，这种HFD诱导的Asm活性、神经酰胺产生、Nlrp 3与ASC或Caspase-1共定位、超氧化物（O2·−）产生的增加在Asm−/−或Asm shRNA转染的野生型小鼠中减弱。与炎性小体形成减少一致，在喂食HFD的Asm−/−或Asm shRNA转染的野生型小鼠中，caspase-1活性和IL-1β产生显著减弱。形态学检查显示，HFD诱导Asm+/+小鼠肾小球的严重损伤，而Asm−/−小鼠的损伤明显减弱。Asm−/−小鼠的肾小球损伤指数降低伴随着蛋白尿减少。使用podocin作为足细胞标记物的荧光免疫组织化学检查显示，由HFD诱导的炎性小体形成主要位于足细胞中，如通过podocin与Nlrp 3的共定位所证明的。总之，这些观察结果揭示了一个关键的作用，Asm在HFD诱导的炎性小体的形成和随之而来的肾小球炎症和损伤。
Ceramide has been reported to initiate inflammasome formation and activation in obesity and different pathological conditions. The present study was performed to explore the role of acid sphingomyelinase (Asm) in the development of high fat diet (HFD)-induced inflammasome and activation and consequent glomerular injury. Asm knockout (Asm−/−) and wild type (Asm+/+) mice with or without Asm short hairpin RNA (shRNA) transfection were fed a HFD or normal chow for 12 weeks to produce obesity and associated glomerular injury. HFD significantly enhanced the Asm activity, ceramide production, colocalization of Nlrp3 (Nod-like receptor protein 3) with ASC (apoptosis-associated speck-like protein) or Caspase-1, NADPH-dependent superoxide (O2•−) production in glomeruli of Asm+/+mice than in control diet-fed mice. However, such HFD-induced increases in Asm activity, ceramide production, colocalization of Nlrp3 with ASC or Caspase-1, superoxide (O2•−) production was attenuated in Asm−/− or Asm shRNA-transfected wild-type mice. In consistency with decreased inflammasome formation, the caspase-1 activity and IL-1β production was significantly attenuated in Asm−/− or Asm shRNA-transfected wild-type mice fed a HFD. Morphological examinations showed that HFD-induced profound injury in glomeruli of Asm+/+ mice which was markedly attenuated in Asm−/− mice. The decreased glomerular damage index in Asm−/− mice was accompanied by attenuated proteinuria. Fluorescent immunohistochemical examinations using podocin as a podocyte marker showed that inflammasome formation induced by the HFD were mostly located in podocytes as demonstrated by co-localization of podocin with Nlrp3. In conclusion, these observations disclose a pivotal role of Asm in the HFD-induced inflammasome formation and consequent glomerular inflammation and injury.