厄贝沙坦通过激活 Nrf2/Keap1 通路和抑制 NLRP3 炎症小体在体内和体外改善糖尿病肾病。

Irbesartan ameliorates diabetic nephropathy by activating the Nrf2/Keap1 pathway and suppressing NLRP3 inflammasomes in vivo and in vitro.

机构信息

State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Department of Endocrinology and Department of Interventional Therapy of First Hospital of Jilin University, Jilin University, Changchun 130000, China; Innovation Pharmaceutical Research Institute of Shijiazhuang No. 4 Pharmaceutical Co., Ltd.；Hebei Guangxiang Pharmaceutical Co., Ltd., Shijiazhuang, 050000, China; Hebei Normal University, Shijiazhuang 050000, China.

出版信息

Int Immunopharmacol. 2024 Apr 20;131:111844. doi: 10.1016/j.intimp.2024.111844. Epub 2024 Mar 18.

DOI:10.1016/j.intimp.2024.111844

PMID:38503013

Abstract

OBJECTIVES

Diabetic nephropathy (DN) is characterized by albuminuria and renal dysfunction caused by diabetes. At present there is no specific treatment for DN. Irbesartan (IRB) is an angiotensin receptor inhibitor indicated for the treatment of hypertension and DN. However, the underlying molecular mechanisms of IRB on DN remains obscure.

METHODS

RAW264.7 macrophages were incubated in RPMI-1640, cell viability was evaluated by CCK-8 assays, transcriptional level of proinflammatory cytokines and was measured by ELISA and qPCR, NLRP3 inflammasome and Nrf2/Keap1 related proteins were measured by Western blotting and immunohistochemistry. Streptozotocin (STZ)-induced diabetic male C57BL/6 mice were used to evaluate the therapeutic effect of IRB on DN. Key findings First, we found that IRB improved high glucose-induced cell inflammation by inhibiting the transcription of IL-1β and IL-18. IRB activated the Nrf2/Keap1 pathway and decreased the release of reactive oxygen species (ROS). IRB also suppressed the expression of NLRP3 and caspase-1. IRB combined with the N-acetylcysteine (NAC) significantly inhibited the activation of NLRP3 inflammasomes. Conversely, IRB combined with the Nrf2-related inhibitor ML385 enhanced NLRP3 inflammasome activation, suggesting that IRB suppressed NLRP3 inflammasome via the Nrf2 pathway. In vivo study, HE staining and immunohistochemistry analysis further showed that IRB ameliorated high glucose-induced renal injury by elevating the expression of the Nrf2/Keap1 signaling pathway and suppressing the proinflammatory cytokine and NLRP3 inflammasome activation.

CONCLUSIONS

Our results suggested that IRB ameliorates diabetic nephropathy by activating the Nrf2/Keap1 pathway and suppressing the NLRP3 inflammasomes in vivo and in vitro. These findings provide new therapeutic strategies of diabetic nephropathy.

摘要

目的

糖尿病肾病（DN）的特征是白蛋白尿和由糖尿病引起的肾功能障碍。目前，DN 没有特定的治疗方法。厄贝沙坦（IRB）是一种血管紧张素受体抑制剂，用于治疗高血压和 DN。然而，IRB 对 DN 的潜在分子机制尚不清楚。

方法

用 RPMI-1640 孵育 RAW264.7 巨噬细胞，用 CCK-8 测定细胞活力，用 ELISA 和 qPCR 测定促炎细胞因子的转录水平，用 Western blot 和免疫组化测定 NLRP3 炎性小体和 Nrf2/Keap1 相关蛋白。用链脲佐菌素（STZ）诱导的糖尿病雄性 C57BL/6 小鼠评估 IRB 对 DN 的治疗作用。主要发现：首先，我们发现 IRB 通过抑制 IL-1β和 IL-18 的转录来改善高糖诱导的细胞炎症。IRB 激活了 Nrf2/Keap1 通路并减少了活性氧（ROS）的释放。IRB 还抑制了 NLRP3 和 caspase-1 的表达。IRB 与 N-乙酰半胱氨酸（NAC）联合显著抑制 NLRP3 炎性小体的激活。相反，IRB 与 Nrf2 相关抑制剂 ML385 联合增强了 NLRP3 炎性小体的激活，表明 IRB 通过 Nrf2 通路抑制 NLRP3 炎性小体。体内研究进一步表明，HE 染色和免疫组化分析显示，IRB 通过上调 Nrf2/Keap1 信号通路和抑制促炎细胞因子和 NLRP3 炎性小体的激活，改善了高糖诱导的肾损伤。