Astaxanthin protects against early acute kidney injury in severely burned rats by inactivating the TLR4/MyD88/NF-κB axis and upregulating heme oxygenase-1

Abstract

Early acute kidney injury (AKI) contributes to severe morbidity and mortality in critically burned patients. Renal inflammation plays a vital role in the progression of early AKI, acting as a therapeutic target. Astaxanthin (ATX) is a strong antioxidant widely distributed in marine organisms that exerts many biological effects in trauma and disease. ATX is also suggested to have anti-inflammatory activity. Hence, we attempted to explore the role of ATX in protecting against early postburn AKI via its anti-inflammatory effects and the related mechanisms. A severely burned model was established for histological and biochemical assessments based on adult male rats. We found that oxidative stress-induced tissue inflammation participated in the development of early AKI after burn injury and that the MyD88-dependent TLR4/NF-κB pathway was activated to regulate renal inflammation. The TLR4 and NF-κB inhibitors TAK242 and PDTC showed similar effects in attenuating burn-induced renal inflammation and early AKI. Upon ATX treatment, the release of inflammatory mediators in the kidneys was downregulated, while the TLR4/MyD88/NF-κB axis was inhibited in a dose-related manner. TAK242 and PDTC could enhance the anti-inflammatory effect of high-dose ATX, whereas lipopolysaccharide (LPS) reversed its action. Furthermore, the expression of heme oxygenase (HO)-1 was upregulated by ATX in a dose-related manner. Collectively, the above data suggest that ATX protects against renal inflammation in a dose-related manner by regulating the TLR4/MyD88/NF-κB axis and HO-1 and ultimately prevents early AKI following severe burns.

Astaxanthin as a Modulator of Nrf2, NF-κB, and Their Crosstalk: Molecular Mechanisms and Possible Clinical Applications

“…Suzuki et al demonstrated that AST has a dose-dependent ocular anti-inflammatory effect through suppression of NO, TNF-α, and prostaglandin E2 (PGE2) production, which occurs by blocking the NF-κB transcription factor [105]. Similarly, another study demonstrated that AST reduced renal inflammation in a dose-related manner by regulating the NF-κB pathway and HO-1, ultimately preventing acute kidney injury [106]. Other authors have reported that AST inhibited NF-κB and Wnt/β-catenin signaling pathways in hepatocellular carcinoma cells and in a hamster model of oral cancer [103,107].…”

Evaluation of Alpha-Ketoglutarate Supplementation on the Improvement of Intestinal Antioxidant Capacity and Immune Response in Songpu Mirror Carp (Cyprinus carpio) After Infection With Aeromonas hydrophila

“…However, the important thing that gets overlooked is that tolllike receptor 4 (TLR4), as one of the important receptors for inflammation recognition, activates the myeloid differentiation factor 88 (MyD88)-dependent pathway, which in turn activates nuclear factor kappa B (NF-kB), and ultimately leads to the release of inflammatory mediators and cytokines, thus playing an antiinflammatory immunomodulatory role (20,21). A growing number of studies have shown that the TLR4/MyD88/NF-kB signaling pathways play a key role in the pathogenesis and treatment of a variety of diseases (22)(23)(24). The innate immune response induces an inflammatory response, which is primarily mediated by cytokines, and the crucial pro-inflammatory cytokines, such as tumor necrosis factor a (TNF-a) and interleukin 8 (IL-8), possess the capabilities of increasing the synthesis of small inflammatory mediators and initiating inflammatory processes.…”

Anti-Inflammatory and Anticancer Effects of Microalgal Carotenoids

“…Another paper demonstrated that ATX liposomes attenuated LPS-induced acute liver injury in rats, reporting a higher antioxidant and anti-inflammatory activity than free ATX due to an enhancement of its oral bioavailability [230]. In the same line, treatment with ATX (5, 10 and 20 mg/kg) dose-dependently protected against burn-induced acute kidney inflammation through suppression of the TLR4/NF-κB pathway and an increase in HO-1 levels [231].…”