Punicalagin Protects Diabetic Nephropathy by Inhibiting Pyroptosis Based on TXNIP/NLRP3 Pathway
Punicalagin Protects Diabetic Nephropathy by Inhibiting Pyroptosis Based on TXNIP/NLRP3 Pathway
复制标题
石榴皮鞣花苷基于TXNIP/NLRP3通路抑制细胞焦亡从而对糖尿病肾病起保护作用
DOI：
10.3390/nu12051516
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发表时间：
2020-05-01
期刊：
影响因子：
5.9
通讯作者：
Yang, Lina
中科院分区：
文献类型：
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作者：
An, Xin;Zhang, Yahui;Yang, Lina
糖尿病肾病是由慢性炎症引起的糖尿病并发症。作为石榴中的主要多酚，安石榴苷被认为具有显著的抗炎特性。本研究建立了高脂饮食（HFD）/链脲佐菌素（STZ）诱导的小鼠糖尿病模型，以验证安石榴苷的体内保护作用。结果显示，安石榴苷干预后，糖尿病小鼠血尿素氮（BUN）、血清肌酐（CREA）、尿白蛋白/肌酐比值（UACR）均显著降低，肾小球间质增生和肾小球肥大症状减轻。细胞凋亡是炎症反应中细胞程序性死亡的一种重要方式;脓毒症相关蛋白如白细胞介素-1（IL-1 β），半胱氨酰谷氨酸特异性蛋白酶-1（caspase-1）、gasdermin D（GSDMD）和核苷酸结合寡聚化结构域、富含亮氨酸重复序列和pyrin结构域的蛋白3（NLRP 3）在我们的研究中减少，证明安石榴苷给药8周可显著抑制小鼠的焦亡。此外，安石榴苷降低了高糖介导的烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶4（NOX 4）的蛋白表达，并减轻了线粒体损伤。NOX 4的低表达抑制了硫氧还蛋白（Trx）和硫氧还蛋白相互作用蛋白（TXNIP）的解离以及NLRP 3炎性小体激活的抑制。总而言之，我们的研究提供了证据表明安石榴苷可以缓解糖尿病肾病，并且该作用与下调NOX 4的表达、抑制TXNIP/NLRP 3途径介导的焦亡有关，表明其对糖尿病并发症的治疗意义。
Diabetic nephropathy is a diabetic complication caused by chronic inflammation. As the primary polyphenol in pomegranate, punicalagin is believed to have significant anti-inflammatory properties. In this study, we established a mice model for diabetes induced by high-fat diet (HFD)/ streptozotocin (STZ) to verify the protective effect of punicalagin in vivo. The results show that the blood urea nitrogen (BUN), serum creatinine (CREA), and the urine albumin to creatinine ratio (UACR) were significantly decreased in diabetic mice after punicalagin intervention, and the symptoms of glomerular interstitial hyperplasia and glomerular hypertrophy were alleviated. Pyroptosis is an essential manner of programmed cell death in the inflammatory response; the expression of pyroptosis-related proteins such as interleukin-1 (IL-1 beta), cysteinyl aspartate-specific protease-1 (caspase-1), gasdermin D (GSDMD), and nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing protein 3 (NLRP3) was decreased in our study, which proved that the administration of punicalagin for eight weeks can significantly inhibit pyroptosis in mice. In addition, punicalagin reduced high glucose-mediated protein expressions of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) and alleviated mitochondria damage. Low expression of NOX4 inhibits the dissociation of thioredoxin (Trx) and thioredoxin-interacting protein (TXNIP) and the suppression of NLRP3 inflammasome activation. To summarize, our study provided evidence that punicalagin can alleviate diabetic nephropathy, and the effect is associated with downregulating the expression of NOX4, inhibiting TXNIP/NLRP3 pathway-mediated pyroptosis, suggesting its therapeutic implications for complications of diabetes.