Inflammation reaction mediated by NLRP3 inflammasome and Nrf2-related oxidative stress are vital participants in the development of diabetic nephropathy (DN) and closely associated to kidney fibrosis. Nrf2, a known antioxidative transcription factor, has been reported to activate NLRP3 inflammasome through its downstream factors (HO-1, NQO1, etc.) recently. AB38b is a newly synthesized biphenyl diester derivative with a Nrf2 activation property. This research aims to evaluate the renal protective effects of AB-38b and to elucidate the anti-inflammation mechanisms involved. Type 2 diabetic mice induced by high fat diet with streptozocin (STZ) and high glucose-cultured mouse glomerular mesangial cells (GMCs) were used in current study. Results showed that administration of AB-38b improved the kidney function while attenuated renal fibrosis progression in diabetic mice together with reducing the extracellular matrix (ECM) accumulation of GMCs cultured in high glucose. Mechanistically, treatment with AB-38b significantly decreased the high level of NLRP3 inflammasome in diabetic condition by inhibiting the ROS/TXNIP/NLRP3 signaling pathway. And meanwhile, AB-38b treatment effectively improved Nrf2 signaling during diabetic condition. Furthermore, knocking down the gene expression of Nrf2 by siRNA in GMCs abolished the inhibition effect of AB-38b on NLRP3 inflammasome activation and ECM accumulation. Taken together, our data suggest that AB-38b was able to improve the renal function of diabetic mice, and the NLRP3 inflammasome inhibition effect of AB-38b was responsible for the renal protective effect. Further exploration indicate that Nrf2 plays pivotal role in AB-38b’s attenuation of DN progression through inhibiting NLRP3 inflammasome activation.

中文翻译：

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新型联苯二酯衍生物 AB-38b 通过糖尿病肾病中的 Nrf2 激活抑制 NLRP3 炎性体。

由 NLRP3 炎症小体和 Nrf2 相关的氧化应激介导的炎症反应是糖尿病肾病 (DN) 发展的重要参与者，并且与肾纤维化密切相关。Nrf2 是一种已知的抗氧化转录因子，最近据报道通过其下游因子（HO-1、NQO1 等）激活 NLRP3 炎性体。AB38b 是一种新合成的具有 Nrf2 活化特性的联苯二酯衍生物。本研究旨在评估 AB-38b 的肾脏保护作用并阐明所涉及的抗炎机制。本研究使用链脲佐菌素 (STZ) 和高葡萄糖培养的小鼠肾小球系膜细胞 (GMC) 诱导的 2 型糖尿病小鼠。结果表明，AB-38b 的给药改善了肾功能，同时减轻了糖尿病小鼠的肾纤维化进展，同时减少了在高葡萄糖中培养的 GMC 的细胞外基质 (ECM) 积累。从机制上讲，AB-38b 治疗通过抑制 ROS/TXNIP/NLRP3 信号通路显着降低糖尿病状态下高水平的 NLRP3 炎性体。同时，AB-38b 治疗有效改善了糖尿病状态下的 Nrf2 信号传导。此外，通过 siRNA 在 GMCs 中敲低 Nrf2 的基因表达消除了 AB-38b 对 NLRP3 炎性体激活和 ECM 积累的抑制作用。总之，我们的数据表明 AB-38b 能够改善糖尿病小鼠的肾功能，AB-38b的NLRP3炎性体抑制作用是肾脏保护作用的原因。进一步探索表明，Nrf2 通过抑制 NLRP3 炎性体激活在 AB-38b 减缓 DN 进展中起关键作用。