1. INTRODUCTION
Acute kidney injury (AKI) is featured by a sharp decline and even loss of kidney function, and the eventual development of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) (Ryter et al. , 2015; Pak et al. , 2020). AKI is not a mere singular organ injury, there is increasing evidence that acute kidney injury directly contributes to remote injury in the lung, heart, liver, immunologic, and other organ systems (Gumbert et al. , 2020). Acute lung injury (ALI) is characterized by rapid alveolar injury and respiratory disorder, which may develop into its most severe form acute respiratory distress syndrome (ARDS) (Nie et al. , 2019). Both AKI and ALI are diseases with high morbidity and mortality and high healthcare costs (Badamjav et al. , 2020; Pak et al. , 2020). Despite extensive efforts and substantial large-scale clinical trials have been made to develop effective therapeutic strategies for AKI and ALI. There are still no approved methods or agents to protect against AKI and ALI are available at present, which highlights the urgent require for the identifying novel pharmacological drugs for AKI and ALI (Zeng et al. , 2017; Jiang et al. , 2019).
Epidemiological analysis has shown that sepsis is common pathology of AKI and ALI patients (Silveira et al. , 2021). Sepsis is manifested by systemic inflammation, leading to multiple organs dysfunction, and the kidneys and lungs are the most vulnerable organs (Ibrahim et al. , 2020). Lipopolysaccharide (LPS) also known as toxic constituent of Gram-negative bacterial, is a crucial pathogenic factor of sepsis. LPS has widely been applied to mimic sepsis-related AKI and ALI in animal models via activating cascade inflammatory responses and synthesis of enormous cytokines, which exhibit similar pathological changes to those found in human infectious sepsis (Juet al. , 2018; Islam et al. , 2019). Inflammation is usually recognized as a defensive response against various invasion, however excessive inflammation always cause extensive tissue or organ injury and even systemic dysfunction (Nie et al. , 2019). Inflammatory cells infiltration and generation of pro-inflammatory cytokines play a pivotal role in the pathogenesis of AKI and ALI (Islam et al. , 2019; Nie et al. , 2019). Strategies targeting the exaggerated inflammatory response resulted in reduction of the damage severity of AKI and ALI. Anti-inflammatory drugs may be an effective option for the prevention of LPS-induced septic AKI and ALI (Chen et al. , 2019; Silveira et al. , 2021).
The nuclear factor-kappa B (NF-κB) is a crucial transcriptional factor controlling genes that encode for various pro-inflammatory cytokines, such as tumour necrosis factor α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) and monocyte chemoattractant protein (MCP) 1, which is a critical target for the development of anti‑inflammatory agents. Numerous compounds have been screened for anti‑inflammatory activities by suppressing NF-κB (Huanget al. , 2019). NF-κB exists in an inactive form in the cytoplasm bound to the B-cells inhibitor alpha (IκB-α). Upon a series of activation after LPS stimulation, IκB kinase (IKK) would be activated, leading to IκB-α activation and degradation, and the dissociated NF-κB could translocate into the nucleus and promote the transcription of inflammatory mediators (Zhang et al. , 2018b). Accumulating evidence suggests that NF-κB signaling pathway plays a significant role in LPS-induced septic AKI and ALI mice, and NF-κB is an attractive therapeutic target for LPS-induced septic AKI and ALI (Huang et al. , 2019; Ibrahim et al. , 2020).
In our study, a series of NF-κB inhibitors were designed and synthesized, and we screened their anti-inflammatory activity using an NF-κB reporter assay. We found 270 exhibited better inhibitory effect, and suppressed the LPS-induced inflammation response in vitro through disturbing NF-κB and JNK signaling pathway. Furthermore, we evaluated the protective abilities of 270 on LPS-induced septic AKI and ALI mice and explored its underlying molecular mechanisms in vivo. The purpose of this study is to provide a novel anti-inflammation drug for the treatment of AKI and ALI.