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The Protein Kinase R Inhibitor C16 Alleviates Sepsis-Induced Acute Kidney Injury Through Modulation of the NF-κB and NLR Family Pyrin Domain-Containing 3 (NLPR3) Pyroptosis Signal Pathways

Jialu Zhou, Fan Zhang, Hongru Lin, Minxue Quan, Yaqin Yang, Yanni Lv, Zongnan He, Yisong Qian

National Engineering Research Center for Bioengineering Drugs and The Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, China (mainland)

Med Sci Monit 2020; 26:e926254

DOI: 10.12659/MSM.926254

Available online: 2020-08-18

Published: 2020-10-05

BACKGROUND: Protein kinase R (PKR) is implicated in the inflammatory response to bacterial infection while the role of PKR in sepsis-induced acute kidney injury (AKI) is largely unknown. This study aimed to investigate the effects of the specific PKR inhibitor C16 (C13H8N4OS) on lipopolysaccharide (LPS)-induced AKI, and its mechanisms of action.
MATERIAL AND METHODS: C57BL/6J mice were injected intraperitoneally with C16 or vehicle 1 h before the LPS challenge and then injected intraperitoneally with LPS or 0.9% saline. After the LPS challenge, histopathological damage, renal function, and levels of proinflammatory cytokines were assessed. All the related signaling pathways were analyzed.
RESULTS: C16 effectively inhibited LPS-induced renal elevation of proinflammatory cytokines and chemokines. C16 prevented NF-kappaB activation and suppressed the PKR/eIF2alpha signaling pathway in AKI after the LPS challenge. Furthermore, C16 significantly inhibited pyroptosis during AKI, as evidenced by decreased renal levels of apoptosis-associated speck-like protein; NACHT, LRR, NLR Family Pyrin Domain-Containing 3; caspase-1; interleukin (IL)-1ß; and IL-18.
CONCLUSIONS: Our findings suggest that inhibition by C16 ameliorated LPS-induced renal inflammation and injury, at least partly through modulation of the pyroptosis signal pathway in the kidney.

Keywords: acute kidney injury, Inflammasomes, Lipopolysaccharides, NF-kappa B