European journal of pharmacology · 2025
The ameliorative effect of inhibiting transient receptor potential ankyrin 1 on sepsis-induced kidney injury via the toll-like receptor 4/nuclear factor-kappa B pathway.
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Fırat Semanur, Çakır Murat, Aydın Ali, Bircan Burak, Şekerci Güldeniz, Tekin Suat
Аннотация
BACKGROUND: Kidneys are among the organs most affected by sepsis caused by the host's uncontrolled immune response to infection. Transient receptor potential ankyrin 1 (TRPA1) channels have been shown to be associated with renal damage. TRPA1 channels also have a role in regulating intracellular Ca2+ levels, cytokine production, and immune response control. In this study, the effects of TRPA1 agonist ASP7663 and antagonist HC-030031 on renal injury in an experimental sepsis model were examined.
MATERIALS AND METHODS: Rats underwent cecal ligation and perforation (CLP) to serve as an experimental sepsis model. One of the two treatment groups received a TRPA1 agonist ASP7663, while the other received a TRPA1 antagonist HC030031. Serum levels of BUN, creatinine (Cre), TNF-α, IL-1β, IL-18, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) were measured. Histopathological examination of kidney tissue was performed. Immunohistochemical analysis of Toll-like receptor 4 (TLR4), NF-κB, phosphorylated NF-κB, IκB-α, phosphorylated IκB-α, TNF-α, IL-1β, IL-6, caspase-3, and caspase-8 levels was conducted in kidney tissue.
RESULTS: CLP administration raised serum levels of BUN, Cre, TNF-α, IL-1β, IL-18, NGAL, and KIM-1 (P < 0.05). It also caused histopathological damage to kidney tissue. Additionally, CLP increased levels of TLR4, phosphorylated NF-κB, phosphorylated IκB-α, TNF-α, IL-1β, IL-6, caspase-3, and caspase-8 in kidney tissue (P < 0.05). The TRPA1 antagonist HC-030031 reversed all pathological changes in serum and kidney tissue caused by CLP.
CONCLUSION: TRPA1 antagonist HC-030031 showed a protective effect in an experimental sepsis model by reducing kidney damage through its anti-inflammatory and anti-apoptotic effects.
MATERIALS AND METHODS: Rats underwent cecal ligation and perforation (CLP) to serve as an experimental sepsis model. One of the two treatment groups received a TRPA1 agonist ASP7663, while the other received a TRPA1 antagonist HC030031. Serum levels of BUN, creatinine (Cre), TNF-α, IL-1β, IL-18, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) were measured. Histopathological examination of kidney tissue was performed. Immunohistochemical analysis of Toll-like receptor 4 (TLR4), NF-κB, phosphorylated NF-κB, IκB-α, phosphorylated IκB-α, TNF-α, IL-1β, IL-6, caspase-3, and caspase-8 levels was conducted in kidney tissue.
RESULTS: CLP administration raised serum levels of BUN, Cre, TNF-α, IL-1β, IL-18, NGAL, and KIM-1 (P < 0.05). It also caused histopathological damage to kidney tissue. Additionally, CLP increased levels of TLR4, phosphorylated NF-κB, phosphorylated IκB-α, TNF-α, IL-1β, IL-6, caspase-3, and caspase-8 in kidney tissue (P < 0.05). The TRPA1 antagonist HC-030031 reversed all pathological changes in serum and kidney tissue caused by CLP.
CONCLUSION: TRPA1 antagonist HC-030031 showed a protective effect in an experimental sepsis model by reducing kidney damage through its anti-inflammatory and anti-apoptotic effects.