Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
Cell Death Dis. 2017 Oct 26;8(10):e3156. doi: 10.1038/cddis.2017.567.
Renal inflammation contributes to the pathogeneses of hypertension. This study was designed to determine whether B-cell lymphoma 6 (BCL6) attenuates renal NLRP3 inflammasome activation and inflammation and its underlying mechanism. Male spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were used in the present study. Angiotensin (Ang) II or lipopolysaccharides (LPS) was used to induce inflammation in HK-2 cells, a human renal tubular epithelial (RTE) cell line. NLRP3 inflammasome was activated and BCL6 was downregulated in the kidneys of SHR. Either Ang II or LPS suppressed BCL6 expression in HK-2 cells. BCL6 overexpression in HK-2 cells attenuated Ang II-induced NLRP3 upregulation, inflammation and cell injury. The inhibitory effects of BCL6 overexpression on NLRP3 expression and inflammation were also observed in LPS-treated HK-2 cells. BCL6 inhibited the NLRP3 transcription via binding to the NLRP3 promoter. BCL6 knockdown with shRNA increased NLRP3 and mature IL-1β expression levels in both PBS- or Ang II-treated HK-2 cells but had no significant effects on ASC, pro-caspase-1 and pro-IL-1β expression levels. BCL6 overexpression caused by recombinant lentivirus expressing BCL6 reduced blood pressure in SHR. BCL6 overexpression prevented the upregulation of NLRP3 and mature IL-1β expression levels in the renal cortex of SHR. The results indicate that BCL6 attenuates Ang II- or LPS-induced inflammation in HK-2 cells via negative regulation of NLRP3 transcription. BCL6 overexpression in SHR reduced blood pressure, NLRP3 expression and inflammation in the renal cortex of SHR.
肾炎症导致高血压的发病机制。本研究旨在确定 B 细胞淋巴瘤 6 (BCL6) 是否减弱肾 NLRP3 炎性小体激活和炎症及其潜在机制。本研究使用雄性自发性高血压大鼠 (SHR) 和 Wistar-Kyoto 大鼠 (WKY)。血管紧张素 (Ang) II 或脂多糖 (LPS) 用于诱导人肾小管上皮 (RTE) 细胞系 HK-2 细胞的炎症。SHR 肾脏中 NLRP3 炎性小体被激活，BCL6 下调。Ang II 或 LPS 均抑制 HK-2 细胞中 BCL6 的表达。HK-2 细胞中 BCL6 的过表达减弱了 Ang II 诱导的 NLRP3 上调、炎症和细胞损伤。在 LPS 处理的 HK-2 细胞中也观察到 BCL6 过表达对 NLRP3 表达和炎症的抑制作用。BCL6 通过与 NLRP3 启动子结合抑制 NLRP3 转录。shRNA 敲低 BCL6 增加了 PBS 或 Ang II 处理的 HK-2 细胞中 NLRP3 和成熟的 IL-1β 表达水平，但对 ASC、pro-caspase-1 和 pro-IL-1β 表达水平没有显著影响。表达 BCL6 的重组慢病毒过表达导致 SHR 的血压降低。BCL6 过表达可防止 SHR 肾皮质中 NLRP3 和成熟的 IL-1β 表达水平的上调。结果表明，BCL6 通过负调控 NLRP3 转录来减弱 Ang II 或 LPS 诱导的 HK-2 细胞炎症。SHR 中的 BCL6 过表达降低了 SHR 肾皮质中的血压、NLRP3 表达和炎症。
