Diabetic kidney disease (DKD) is the leading cause of end-stage kidney diseases resulting enormous social-economic burden. Accumulated evidence has indicated that C-reactive protein (CRP) exacerbates DKD by enhancing renal inflammation and fibrosis through TGF-β/Smad3 signaling. NLRP3 inflammasome is the key sensor contributing to renal inflammation. However, whether CRP enhances inflammation in DKD via NLRP3 inflammasome related pathway remains unknown. In this study, we demonstrate that CRP promotes DKD via Smad3-mediated NLRP3 inflammasome activation as mice overexpressing human CRP gene exhibits accelerated renal inflammation in diabetic kidneys, which is associated with the activation of Smad3 and NLRP3 inflammasome. In contrast, blockade of CPR signaling with a neutralizing anti-CD32 antibody attenuates CRP-induced activation of Smad3 and NLRP3 in vitro. Importantly, genetic deletion or pharmacological inhibition of Smad3 also mitigates CRP-induced activation of NLRP3 in diabetic kidneys or in high glucose treated cells. Mechanistically, we reveal that Smad3 binds to the NLRP3 gene promoter which is enhanced by CRP. Taken together, we conclude that CRP induces renal inflammation in DKD via Smad3-NLRP3 inflammasome-dependent mechanism. Thus, targeting CRP or Smad3-NLRP3 pathways may be a new therapeutic potential for DKD.

中文翻译：

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C 反应蛋白通过 Smad3 介导的 NLRP3 炎性小体激活促进糖尿病肾病。


糖尿病肾病 （DKD） 是导致终末期肾病的主要原因，造成巨大的社会经济负担。积累的证据表明，C 反应蛋白 （CRP） 通过 TGF-β/Smad3 信号传导增强肾脏炎症和纤维化，从而加剧 DKD。NLRP3 炎性小体是导致肾脏炎症的关键传感器。然而，CRP 是否通过 NLRP3 炎性小体相关途径增强 DKD 患者的炎症仍不清楚。在这项研究中，我们证明 CRP 通过 Smad3 介导的 NLRP3 炎性小体激活促进 DKD，因为过表达人 CRP 基因的小鼠在糖尿病肾脏中表现出加速的肾脏炎症，这与 Smad3 和 NLRP3 炎性小体的激活有关。相比之下，用中和抗 CD32 抗体阻断 CPR 信号传导会在体外减弱 CRP 诱导的 Smad3 和 NLRP3 激活。重要的是，Smad3 的基因缺失或药理学抑制也减轻了 CRP 诱导的糖尿病肾或高葡萄糖处理细胞中 NLRP3 的激活。从机制上讲，我们揭示了 Smad3 与 NLRP3 基因启动子结合，后者由 CRP 增强。综上所述，我们得出结论，CRP 通过 Smad3-NLRP3 炎性小体依赖性机制诱导 DKD 的肾脏炎症。因此，靶向 CRP 或 Smad3-NLRP3 通路可能是 DKD 的新治疗潜力。