Statins ameliorate cholesterol-induced inflammation and improve AQP2 expression by inhibiting NLRP3 activation in the kidney.

• 影响指数: 11.6
• 发表时间: 2020
• 来源期刊: Theranostics
• DOI: 10.7150/thno.49603
• PMID: 32929357
• 文章类型: Journal Article
• 中科院分区: Q1
• 方向: 医学
• 作者列表: Kong Y,Feng W,Zhao X,Zhang P,Li S,Li Z,Lin Y,Liang B,Li C,Wang W,Huang H

关键词: AQP2; ASC; IL-1β; cholesterol; statins

Mesh: Adult; Animals; Aquaporin 2 / analysis metabolism; Biopsy; Cholesterol / blood metabolism; Diet, High-Fat / adverse effects; Disease Models, Animal; Disease Progression; Dyslipidemias / blood complications drug therapy immunology; Female; Glomerular Filtration Rate; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage; Inflammasomes / antagonists & inhibitors immunology metabolism; Kidney / drug effects immunology pathology; Lipid Metabolism / drug effects immunology; Male; Mice; Mice, Knockout; Middle Aged; NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors genetics metabolism; Rats; Renal Insufficiency, Chronic / blood complications drug therapy immunology; Retrospective Studies

Abstract

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.