Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, China.
Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States.
Front Immunol. 2022 Jul 7;13:925738. doi: 10.3389/fimmu.2022.925738. eCollection 2022.
Chronic inflammation contributes to maladaptive kidney repair, but its regulation is unclear. Here, we report that sirtuin 1 (SIRT1) is downregulated after repeated low-dose cisplatin (RLDC) injury, and this downregulation leads to p65 acetylation and consequent NF-κB activation resulting in a persistent inflammatory response. RLDC induced the down-regulation of SIRT1 and activation of NF-κB, which were accompanied by chronic tubular damage, tubulointerstitial inflammation, and fibrosis in mice. Inhibition of NF-κB suppressed the production of pro-inflammatory cytokines and fibrotic phenotypes in RLDC-treated renal tubular cells. SIRT1 activation by its agonists markedly reduced the acetylation of p65 (a key component of NF-κB), resulting in the attenuation of the inflammatory and fibrotic responses. Conversely, knockdown of SIRT1 exacerbated these cellular changes. At the upstream, p53 was activated after RLDC treatment to repress SIRT1, resulting in p65 acetylation, NF-κB activation and transcription of inflammatory cytokines. In mice, SIRT1 agonists attenuated RLDC-induced chronic inflammation, tissue damage, and renal fibrosis. Together, these results unveil the p53/SIRT1/NF-κB signaling axis in maladaptive kidney repair following RLDC treatment, where p53 represses SIRT1 to increase p65 acetylation for NF-κB activation, leading to chronic renal inflammation.
慢性炎症会导致适应性肾脏修复失败，但目前其调控机制尚不清楚。本文报道了重复低剂量顺铂（RLDC）损伤后，沉默信息调节因子 2 相关酶 1（SIRT1）下调，导致 p65 乙酰化和随之而来的核因子-κB（NF-κB）激活，从而引起持续的炎症反应。RLDC 诱导 SIRT1 下调和 NF-κB 激活，导致小鼠慢性肾小管损伤、肾小管间质性炎症和纤维化。NF-κB 抑制可抑制 RLDC 处理的肾小管细胞中促炎细胞因子和纤维表型的产生。其激动剂激活 SIRT1 可显著减少 p65（NF-κB 的关键成分）的乙酰化，从而减轻炎症和纤维化反应。相反，SIRT1 的敲低则加剧了这些细胞变化。在 RLDC 处理后，p53 被激活以抑制 SIRT1，导致 p65 乙酰化、NF-κB 激活和炎症细胞因子的转录。在小鼠中，SIRT1 激动剂可减轻 RLDC 诱导的慢性炎症、组织损伤和肾脏纤维化。综上所述，这些结果揭示了 RLDC 治疗后适应性肾脏修复失败中的 p53/SIRT1/NF-κB 信号轴，其中 p53 抑制 SIRT1 增加 p65 乙酰化以激活 NF-κB，导致慢性肾脏炎症。
