Astaxanthin protects against early acute kidney injury in severely burned rats by inactivating the TLR4/MyD88/NF-\u03baB axis and upregulating heme oxygenase-1

Songxue Guo,Chuangang You,Meirong Yu,Xingang Wang,Quan Fang,Liping Zhang,Linsen Guo,Chunmao Han,Yong Liu

doi:10.1038/s41598-021-86146-w

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.

Highlights

Abbreviations acute kidney injury (AKI) Acute kidney injury IHC Immunochemistry IKK Inhibitor of nuclear factor kappa-B kinase IκBα Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha IL Interleukin IR Ischemia–reperfusion IP Intraperitoneal injection MyD88 Myeloid differentiation primary response gene 88
In terms of renal function, we observed that burn injury increased the levels of serum creatinine (sCr) and neutrophil gelatinase-associated lipocalin (NGAL) at 6 h post burn injury, and levels peaked at 48 h after burn injury, whereas TAK242 had a stronger effect on attenuating the burn-induced increase in sCr and NGAL than PDTC
Our findings showed the following: (1) burn-induced renal inflammation contributes to the development of early AKI, with a concurrent increase in oxidative stress; (2) the TLR4/Nuclear factor (NF)-κB pathway is involved in regulation of renal inflammation after burn insult and is dependent on MyD88; (3) ATX dose-relatedly attenuates activation of the TLR4/MyD88/NF-κB cascade and the subsequent release of inflammatory mediators; and (4) ATX further upregulates renal expression of heme oxygenase (HO)-1 in a dose-related manner to assist in its regulation of oxidative stress and the TLR4 pathway

Summary

Introduction

Abbreviations AKI Acute kidney injury IHC Immunochemistry IKK Inhibitor of nuclear factor kappa-B kinase IκBα Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha IL Interleukin IR Ischemia–reperfusion IP Intraperitoneal injection MyD88 Myeloid differentiation primary response gene 88. We observed that the selective antioxidant molecular hydrogen may inhibit burn-induced release of inflammatory cytokines in rat kidneys through an NF-κB-mediated signaling pathway and attenuate early AKI and reduce a poptosis[8]. The Toll-like receptor (TLR)4/ NF-κB signaling pathway has been suggested to be a classic cascade that is able to regulate development of the inflammatory response in diverse organ injuries following ischemia–reperfusion (IR)[11]. In terms of burn injury, we observed that ATX exerted a protective effect against burn-induced early AKI by ameliorating oxidative damage and downregulating mitochondria-related apoptosis via the PI3K/Akt/Bad pathway[7]. Combined with similar reports of its effects on oxidative damage and inflammation in other organ injuries, ATX seems to be a promising and nontoxic therapeutic reagent to prevent early AKI after burn injury[20,21]

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Conclusion