Saroglitazar, a dual PPAR-α/γ agonist, alleviates LPS-induced hepatic and renal injury in rats

• Published in: International immunopharmacology 2023-02, Vol.115, p.109688, Article 109688
• Main Authors: Francis, Marina R., El-Sheakh, Ahmed R., Suddek, Ghada M.
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - chemically induced; Acute Kidney Injury - drug therapy; Acute Kidney Injury - metabolism; Animals; Anti-Inflammatory Agents - therapeutic use; Caspase-11; Glutathione - metabolism; GSDMD; Inflammasomes - metabolism; Kidney; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Liver - metabolism; NF-kappa B - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3; Peroxisome Proliferator-Activated Receptors - metabolism; Pyroptosis; Rats; Saroglitazar
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2023.109688

Ⅰ: Graphical abstract representing an overview of LPS-induced caspase-11-dependent non-canonical inflammasome activation and subsequent activation of NLRP3 inflammasome for cytokine maturation and release resulting in pyroptosis. LPS: lipopolysaccharide, SAR: saroglitazar, TLR4: toll-like receptor 4, MyD88: Myeloid differentiation primary response 88, TRIF: TIR-domain-containing adapter-inducing interferon-β, NF-κB: nuclear factor-kappa B, p-IκBα: phosphorylated inhibitor of kappa B alpha, IRF3: interferon regulatory factor 3, NLRP3: Nucleotide-Binding Oligomerization Domain (NOD)-Like Receptor Protein 3, IL-1β: interlukin-1 beta, HMGB-1: high mobility group box-1, RAGE: receptor for advanced glycation end-products, GSDMD: gasdermin D, MDA: malondialdehyde, SOD: superoxide dismutase, GSH: glutathione, AST: aspartate aminotransferase, ALT: alanine aminotransferase, SCr: serum creatinine, BUN: blood urea nitrogen, KIM-1: kidney injury molecule-1, OMV: outer membrane vesicle. [Display omitted] •Effect of saroglitazar (SAR) on acute hepatic-renal injury mediated by LPS injection was studied.•Saroglitazar improved LPS-induced alterations in hepatic and renal functions.•An antioxidant activity, through a decrease in MDA content and increase in SOD and GSH contents, was found in SAR-treated groups.•Saroglitazar possessed an anti-inflammatory activity by reducing NF-κB and IFN-β expression.•Saroglitazar suppressed caspase-11-dependent non-canonical inflammasome activation and subsequent activation of NLRP3 inflammasome.•Pyroptotic cell death was inhibited upon prophylaxis with SAR by suppressing GSDMD expression and IL-1β release. Lipopolysaccharide (LPS), an endotoxin within gram-negative bacteria, is associated with systemic acute inflammatory response after invading living tissues and results in sepsis. The liver and kidney are both major target organs in sepsis. Septic acute hepatic-renal injury is a serious clinical condition with high risk of morbidity and mortality. Nevertheless, effective treatment is still lacking. This study highlights saroglitazar (SAR), a dual PPAR-α/γ agonist, as a proposed prophylactic drug against LPS-induced hepatic-renal injury. Rats were pretreated with SAR (2 and 4 mg/kg/day) for 15 days, while sepsis was induced by LPS injection (10 mg/kg) on day 15 one hour following SAR oral administration. SAR pretreatment could successfully mitigate LPS-induced hepatic-renal injury, evidenced by enhancement of renal and hepatic functions an