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.