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

Abstract

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/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-κB activation and suppressed the PKR/eIF2α 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)-1β; 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.

Angiotensin (1-7) Attenuates Sepsis-Induced Acute Kidney Injury by Regulating the NF-κB Pathway

“…LPS was previously reported to induce the production of TNFα and IL-6 in kidneys of normal rats, and this effect was likely to be aggravated after renal intravenous administration of Ang II (Niimi et al, 2002). LPS stimulates NF-κB, mitogen-activated protein kinase (MAPK) family, and other signals to transmit into cells through binding with CD14 and TLR4, inducing the release of a large number of inflammatory factors, such as TNF-α, IFN-γ, IL-1, IL-6, and IL-12 (Smith et al, 2015;Patel et al, 2019;Zhou et al, 2020). These inflammatory factors are generally signal molecules and effectors that directly result in "inflammatory storm" through the NF-κB pathway, leading to cell damage.…”

Identifying Candidate Protein Markers of Acute Kidney Injury in Acute Decompensated Heart Failure

“…These included two pathways with established roles in AKI [28,29]: the glycoprotein VI (GP6) signalling pathway (pro-inflammatory, activated between Baseline and ADHF), and the acute phase response signalling pathway (proinflammatory, inhibited between ADHF and Recovery). Enriched pathways previously implicated in AKI that were repressed between Baseline and ADHF included the xenobiotic pregnane X receptor (PXR) signalling pathway (anti-inflammatory) [30,31], the xenobiotic metabolism aryl hydrocarbon receptor (AHR) signalling pathway (anti-proliferation, proinflammatory) [32,33], the peroxisome proliferator-activated receptor alpha (PPARα/RXRα) pathway (anti-inflammatory) [34,35], and the protein kinase R (PKR) in interferon induction and antiviral response pathway (pro-apoptotic, pro-inflammatory) [36,37]. The coagulation system, also implicated in AKI [38,39], was activated between Baseline and ADHF.…”

“…The coagulation system, also implicated in AKI [38,39], was activated between Baseline and ADHF. metabolism aryl hydrocarbon receptor (AHR) signalling pathway (anti-proliferation, proinflammatory) [32,33], the peroxisome proliferator-activated receptor alpha (PPARα/RXRα) pathway (anti-inflammatory) [34,35], and the protein kinase R (PKR) in interferon induction and antiviral response pathway (pro-apoptotic, pro-inflammatory) [36,37]. The coagulation system, also implicated in AKI [38,39], was activated between Baseline and ADHF.…”

Protein Kinase R in Bacterial Infections: Friend or Foe?

“…Furthermore, several in vivo studies using mice and rats have examined the effect of C16 in disease contexts such as inflammation, neurodegeneration, obesity, hypertension, cancer, and diabetes (170-184) (Table 2). Importantly, numerous groups have shown that C16 is protective of LPS-induced pathogenesis in mice, including acute lung injury, bone destruction, skeletal muscle atrophy, and acute kidney injury (177)(178)(179)(180)(181). Since LPS is a major cell wall component of Gram-negative bacteria, these findings suggest that C16 could protect against excessive inflammation and tissue damage during bacterial infections.…”