Institute of Food Science and Engineering, Hangzhou Medical College, Tianmushan Road 182th, Hangzhou, Zhejiang, PR China.
Hangzhou Red Cross Hospital, Chengdong Road 208th, Hangzhou, Zhejiang, PR China.
Biomed Pharmacother. 2022 Jun;150:112998. doi: 10.1016/j.biopha.2022.112998. Epub 2022 Apr 27.
Diabetic nephropathy (DN), which is characterized by renal fibrosis, is a major complication of diabetes, a disease that afflicted more than 460 million people worldwide in 2019. Pyroptosis is an essential signaling pathway in DN-related injuries, such as renal fibrosis. Pyrroloquinoline quinone (PQQ) is a naturally occurring bioactive compound that protects human kidney 2 (HK-2) cells from oxidative stress-induced damage caused by high glucose concentrations. However, the nature and underlying mechanism of the effect of PQQ on DN-related renal fibrosis remains unclear. In this study, we evaluated whether PQQ has potential protective effects against renal fibrosis due to DN by establishing type 1 diabetes in mice via streptozotocin treatment and then inhibiting their pyroptosis signaling pathway. We found that compared to control mice, the area of renal fibrosis and injury were significantly increased in diabetic mice, and this was accompanied by increased levels of expression of collagen Ⅰ and transforming growth factor-β1; increased concentrations of the inflammatory cytokines, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α; and activation of the pyroptosis pathway components nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), caspase-1, IL-1β, and IL-18. All of these changes were reversed by PQQ treatment. Analogously, we treated cultured HK-2 cells with a high concentration of glucose (35 mmol/L), which caused these cells to exhibit significantly increased concentrations of reactive oxygen species (ROS), phosphorylated (p)-nuclear factor kappa B (NF-κB), p-IkappaB, NLRP3, caspase-1, IL-1β, and IL-18, and the loss of mitochondrial transmembrane potential. However, PQQ treatment significantly blunted these effects. In conclusion, in this study we demonstrated that PQQ attenuates renal fibrosis by alleviating mitochondrial dysfunction, reducing ROS production, and inhibiting the activation of the NF-κB/pyroptosis pathway under conditions of DN and hyperglycemia.
糖尿病肾病（DN）以肾纤维化为特征，是糖尿病的一种主要并发症，2019 年，全世界有超过 4.6 亿人患有这种疾病。细胞焦亡是与 DN 相关损伤（如肾纤维化）的重要信号通路。吡咯喹啉醌（PQQ）是一种天然存在的生物活性化合物，可保护人肾 2 （HK-2）细胞免受高葡萄糖浓度诱导的氧化应激损伤。然而，PQQ 对 DN 相关肾纤维化的作用性质和潜在机制尚不清楚。在这项研究中，我们通过链脲佐菌素（STZ）处理建立了 1 型糖尿病小鼠模型，评估了 PQQ 是否通过抑制其细胞焦亡信号通路对 DN 相关肾纤维化具有潜在的保护作用。我们发现，与对照组小鼠相比，糖尿病小鼠的肾纤维化和损伤面积明显增加，同时伴有胶原 Ⅰ和转化生长因子-β1表达水平升高；炎症细胞因子白细胞介素（IL）-1β、IL-6 和肿瘤坏死因子-α浓度升高；以及细胞焦亡通路成分核苷酸结合寡聚化结构域样受体家族 pyrin 结构域包含蛋白 3（NLRP3）、半胱氨酸天冬氨酸蛋白酶-1（caspase-1）、IL-1β 和 IL-18 的激活。所有这些变化都被 PQQ 处理所逆转。类似地，我们用高浓度葡萄糖（35mmol/L）处理培养的 HK-2 细胞，导致这些细胞的活性氧（ROS）、磷酸化（p）核因子 kappa B（NF-κB）、p-IκappaB、NLRP3、caspase-1、IL-1β 和 IL-18 浓度显著增加，以及线粒体跨膜电位丧失。然而，PQQ 处理显著减弱了这些作用。总之，在这项研究中，我们证明了 PQQ 通过减轻线粒体功能障碍、减少 ROS 产生和抑制 NF-κB/细胞焦亡通路的激活，在糖尿病和高血糖条件下减轻肾纤维化。
