期刊
SHOCK
卷 57, 期 3, 页码 417-426出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/SHK.0000000000001881
关键词
Acute kidney injury; KLF6; miR-223-3p; NLRP3; Caspase-1; IL-1 beta signaling pathway; oxidative stress; pyroptosis; renal tubular epithelial cell; sepsis
The study found that KLF6 was highly expressed in septic acute kidney injury (SAKI). Knockdown of KLF6 alleviated oxidative stress and pyroptosis in SAKI. Mechanistically, KLF6 inhibited miR-223-3p expression and promoted NLRP3 activation, thereby aggravating SAKI.
Septic acute kidney injury (SAKI) represents a clinical challenge with high morbidity and mortality. The current study aimed to analyze the effects and molecular mechanism of Kruppel-like factor 6 (KLF6) on SAKI. First, SAKI mouse models were established by cecum ligation and puncture, while in vivo cell models were established using lipopolysaccharide (LPS). RT-qPCR assay was subsequently performed to detect the levels of KLF6 mRNA. SAKI mice and LPS-treated TCMK-1 cells were further treated with KLF6 siRNA. Afterward, HE staining, PAS staining, Western blot assay, and ELISA were adopted to ascertain the effects of KLF6 in pyroptosis. The binding relationships between KLF6 and miR-223-3p promoter /miR-223-3p and NLRP3 were analyzed with the help of CHIP and dual-luciferase reporter assays. RT-qPCR was adopted to determine the expression patterns of miR-223-3p and NLRP3. Lastly, a rescue experiment was designed to confirm the role of miR-223-3p. It was found that KLF6 was highly expressed in SAKI, whereas knockdown of KLF6 alleviated oxidative stress (OS) and pyroptosis in SAKI mice and LPS-treated TCMK-1 cells. Mechanistic results confirmed that KLF6 inhibited miR-223-3p via binding to the miR-223-3p promoter and promoted NLRP3. On the other hand, downregulation of miR-223-3p activated the NLRP3/Caspase-1/IL-1 beta pathway and aggravated OS and pyroptosis. Overall, our findings indicated that KLF6 inhibited miR-223-3p via binding to the miR-223-3p promoter and promoted NLRP3, and activated the NLRP3/Caspase-1/IL-1 beta pathway, thereby aggravating pyroptosis and SAKI.
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