Downregulation of IRF2 Alleviates Sepsis-Related Acute Kidney Injury in vitro and in vivo

Abstract

Objective:We investigated the roles and mechanisms of IRF2 in sepsis-related acute kidney injury (S-AKI) in a lipopolysaccharide (LPS)-induced HK-2 cell line and caecal ligation and puncture (CLP)-induced IRF2 −/− mouse model. Methods: Quantitative real-time polymerase chain reaction assay was used to detect IRF2 in the serum of S-AKI patients and LPS-induced HK-2 cells. Cell proliferation, death, and apoptosis were analysed by CCK-8, lactate dehydrogenase release, and flow cytometry assays, respectively. The levels of interleukin (IL)-1β, IL-18, IL-6, tumour necrosis factor (TNF)-α, non-canonical inflammasomes, including caspase-4 and gasdermin-D (GSDMD), and canonical inflammasomes, such as caspase-1, NLR family pyrin domain containing 3 (NLRP3), and apoptosis-associated speck-like protein (ASC) in S-AKI cells or animal models were analysed by enzyme-linked immunosorbent assay or Western blotting. Results: IRF2 was upregulated in the serum of S-AKI patients and LPS-induced HK-2 cells. IRF2 downregulation promoted cell proliferation and inhibited cell death and apoptosis, respectively. IRF2 inhibition reduced the levels of IL-1β, IL-18, IL-6, and TNF-α in S-AKI cells and animal models. IRF2 knockdown inhibited LPS-treated HK-2 cell pyroptosis by decreasing the expression of caspase-4 and GSDMD, instead of affecting caspase-1, NLRP3, and ASC. An elevated survival rate and alleviated pathological features and scores were observed in the CLP-induced IRF2 −/− animal models. IRF2 deficiency also suppressed inflammation and pyroptosis by inhibiting non-canonical inflammasomes as indicated by the decreased expression of caspase-11 and GSDMD. Conclusion: Our findings suggest that IRF2 downregulation protects against S-AKI in vitro and in vivo.

Programmed Cell Death in Sepsis Associated Acute Kidney Injury

“…Guo et al ( 115 ) and Liu et al ( 116 ) found that apoptosis and pyroptosis coexist in CLP mice. Li and Liu confirmed the same results ( 117 , 118 ). Yu et al ( 108 ) found that autophagy existed in a CLP mouse model, in the early stage, autophagy was stronger, and gradually weakened over time.…”

Kaempferol Reverses Acute Kidney Injury in Septic Model by Inhibiting NF-κB/AKT Signaling Pathway

“…In cellular experiments, Zhang et al found that LPS can increase TNF-α and IL-1β expression in HK-2 cells [23]. In this study, HK-2 cells were treated with 10 µg/ml LPS, and TNF-α and IL-1β expression was increased, confrming that LPS can induce infammatory damage in HK-2 cells.…”

miR-181a-5p Inhibits Pyroptosis in Sepsis-Induced Acute Kidney Injury through Downregulation of NEK7

“…There are only two studies reporting this. Zhang et al found that downregulated IRF2 could alleviate S-AKI in vitro and in vivo [ 36 ]. Liu and Wang found that the DRP1 inhibitor could alleviate LPS-reduced S-AKI by inhibiting NLRP3 inflammasome [ 37 ].…”