Obeticholic acid ameliorates sepsis-induced renal mitochondrial damage by inhibiting the NF-κb signaling pathway

• Published in: Renal failure 2024-12, Vol.46 (2), p.2368090
• Main Authors: Jing, Danyang, Liu, Jingfeng, Qin, Da, Lin, Jin, Li, Tian, Li, Yu, Duan, Meili
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury; Acute Kidney Injury - drug therapy; Acute Kidney Injury - etiology; Acute Kidney Injury - metabolism; Acute Kidney Injury - prevention & control; AKI; Animals; Chenodeoxycholic Acid - analogs & derivatives; Chenodeoxycholic Acid - pharmacology; Chenodeoxycholic Acid - therapeutic use; Disease Models, Animal; Inflammasomes - drug effects; Inflammasomes - metabolism; inflammation; Interleukin-1beta - metabolism; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Male; mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; NF-kappa B - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein - antagonists & inhibitors; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; OCA; Oxidative Stress - drug effects; Rats; Rats, Sprague-Dawley; Sepsis; Sepsis - complications; Sepsis - drug therapy; Signal Transduction - drug effects
• ISSN: 0886-022X; 1525-6049; 1525-6049
• DOI: 10.1080/0886022X.2024.2368090

Acute kidney injury (AKI), a common complication of sepsis, might be caused by overactivated inflammation, mitochondrial damage, and oxidative stress. However, the mechanisms underlying sepsis-induced AKI (SAKI) have not been fully elucidated, and there is a lack of effective therapies for AKI. To this end, this study aimed to investigate whether obeticholic acid (OCA) has a renoprotective effect on SAKI and to explore its mechanism of action. Through bioinformatics analysis, our study confirmed that the mitochondria might be a critical target for the treatment of SAKI. Thus, a septic rat model was established by cecal ligation puncture (CLP) surgery. Our results showed an evoked inflammatory response the NF-κB signaling pathway and NLRP3 inflammasome activation in septic rats, which led to mitochondrial damage and oxidative stress. OCA, an Farnesoid X Receptor (FXR) agonist, has shown anti-inflammatory effects in numerous studies. However, the effects of OCA on SAKI remain unclear. In this study, we revealed that pretreatment with OCA can inhibit the inflammatory response by reducing the synthesis of proinflammatory factors (such as IL-1β and NLRP3) blocking NF-κB and alleviating mitochondrial damage and oxidative stress in the septic rat model. Overall, this study provides insight into the excessive inflammation-induced SAKI caused by mitochondrial damage and evidence for the potential use of OCA in SAKI treatment.