Statins ameliorate cholesterol-induced inflammation and improve AQP2 expression by inhibiting NLRP3 activation in the kidney
Statins ameliorate cholesterol-induced inflammation and improve AQP2 expression by inhibiting NLRP3 activation in the kidney
复制标题
他汀类药物通过抑制肾脏中 NLRP3 的激活来改善胆固醇诱导的炎症并改善 AQP2 的表达
DOI：
10.7150/thno.49603
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Huang, Hui
中科院分区：
文献类型：
--
作者：
Kong, Yonglun;Feng, Weijing;Huang, Hui
背景：慢性肾脏病（CKD）通常与血脂异常有关。他汀类药物治疗主要被推荐用于预防CKD患者的心血管风险;然而，他汀类药物对肾脏疾病进展的影响仍存在争议。本研究旨在研究他汀类药物治疗对高脂饮食患者和动物肾脏水处理的影响。研究方法：回顾性队列患者数据进行了审查，水通道蛋白-2（AQP 2）和NLRP 3炎性小体适配器ASC的蛋白表达水平在肾活检标本中进行了检查。在nlrp 3-/-小鼠、高脂饮食（HFD）的5/6肾切除（5/6 Nx）大鼠和体外检查他汀类药物对AQP 2和NLRP 3炎性体组分的影响。结果如下：在回顾性队列研究中，血清胆固醇与肾活检标本中eGFR和AQP 2蛋白表达呈负相关。他汀类药物对eGFR没有影响，但消除了胆固醇和AQP 2表达之间的负相关性。而nlrp 3 +/+小鼠在HFD后显示出增加的尿量和降低的AQP 2蛋白表达，其在患有HFD的nlrp 3缺失小鼠中中度减弱。在HFD的5/6 Nx大鼠中，阿托伐他汀显著减少尿量并上调AQP 2的蛋白表达。胆固醇刺激NLRP 3炎性体组分ASC、caspase-1和IL-1β的蛋白表达，并在体外降低AQP 2蛋白丰度，这被他汀类药物显著阻止，可能是通过自噬增强ASC斑点降解。结论：肾活检组织中AQP 2蛋白表达与血清胆固醇水平呈负相关。他汀类药物可以通过促进ASC斑的降解来改善胆固醇诱导的炎症，并提高HFD动物肾脏水通道蛋白的表达。
Background: Chronic kidney diseases (CKD) are usually associated with dyslipidemia. Statin therapy has been primarily recommended for the prevention of cardiovascular risk in patients with CKD; however, the effects of statins on kidney disease progression remain controversial. This study aims to investigate the effects of statin treatment on renal handling of water in patients and in animals on a high-fat diet. Methods: Retrospective cohort patient data were reviewed and the protein expression levels of aquaporin-2 (AQP2) and NLRP3 inflammasome adaptor ASC were examined in kidney biopsy specimens. The effects of statins on AQP2 and NLRP3 inflammasome components were examined in nlrp3-/- mice, 5/6 nephroectomized (5/6Nx) rats with a high-fat diet (HFD), and in vitro. Results: In the retrospective cohort study, serum cholesterol was negatively correlated to eGFR and AQP2 protein expression in the kidney biopsy specimens. Statins exhibited no effect on eGFR but abolished the negative correlation between cholesterol and AQP2 expression. Whilst nlrp3+/+ mice showed an increased urine output and a decreased expression of AQP2 protein after a HFD, which was moderately attenuated in nlrp3 deletion mice with HFD. In 5/6Nx rats on a HFD, atorvastatin markedly decreased the urine output and upregulated the protein expression of AQP2. Cholesterol stimulated the protein expression of NLRP3 inflammasome components ASC, caspase-1 and IL-1β, and decreased AQP2 protein abundance in vitro, which was markedly prevented by statins, likely through the enhancement of ASC speck degradation via autophagy. Conclusion: Serum cholesterol level has a negative correlation with AQP2 protein expression in the kidney biopsy specimens of patients. Statins can ameliorate cholesterol-induced inflammation by promoting the degradation of ASC speck, and improve the expression of aquaporin in the kidneys of animals on a HFD.