title: Sialic acid rescues repurified lipopolysaccharide-induced acute renal failure via inhibiting TLR4/PKC/gp91-mediated endoplasmic reticulum stress, apoptosis, autophagy, and pyroptosis signaling.
abstract: Lipopolysaccharides (LPS) through Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) activation induce systemic inflammation where oxidative damage plays a key role in multiple organ failure. Because of the neutralization of LPS toxicity by sialic acid (SA), we determined its effect and mechanisms on repurified LPS (rLPS)-evoked acute renal failure. We assessed the effect of intravenous SA (10 mg/kg body weight) on rLPS-induced renal injury in female Wistar rats by evaluating blood and kidney reactive oxygen species (ROS) responses, renal and systemic hemodynamics, renal function, histopathology, and molecular mechanisms. SA can interact with rLPS through a high binding affinity. rLPS dose- and time-dependently reduced arterial blood pressure, renal microcirculation and blood flow, and increased vascular resistance in the rats. rLPS enhanced monocyte/macrophage (ED-1) infiltration and ROS production and impaired kidneys by triggering p-IRE1α/p-JNK/CHOP/GRP78/ATF4-mediated endoplasmic reticulum (ER) stress, Bax/PARP-mediated apoptosis, Beclin-1/Atg5-Atg12/LC3-II-mediated autophagy, and caspase 1/IL-1β-mediated pyroptosis in the kidneys. SA treatment at 30 min, but not 60 min after rLPS stimulation, gp91 siRNA and protein kinase C-α (PKC) inhibitor efficiently rescued rLPS-induced acute renal failure via inhibition of TLR4/PKC/NADPH oxidase gp91-mediated ER stress, apoptosis, autophagy and pyroptosis in renal proximal tubular cells, and rat kidneys. In response to rLPS or IFNγ, the enhanced Atg5, FADD, LC3-II, and PARP expression can be inhibited by Atg5 siRNA. Albumin (10 mg/kg body weight) did not rescue rLPS-induced injury. In conclusion, early treatment (within 30 min) of SA attenuates rLPS-induced renal failure via the reduction in LPS toxicity and subsequently inhibiting rLPS-activated TLR4/PKC/gp91/ER stress/apoptosis/autophagy/pyroptosis signaling.
authors: Department of Internal Medicine, National Yang-Ming University, Taipei 11221, Taiwan Department of Family Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.
authors: Chih-Ching
authors: CC
authors: Yang
authors: National Taiwan University Hospital and College of Medicine, Taipei 10016, Taiwan.
authors: Chien-An
authors: CA
authors: Yao
authors: Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan ctchien@ntnu.edu.tw.
authors: Jyh-Chin
authors: JC
authors: Yang
authors: Department of Planning, Ministry of Health and Welfare, Executive Yuan, Taipei 11558, Taiwan ctchien@ntnu.edu.tw.
authors: Chiang-Ting
authors: CT
authors: Chien
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5; D015153:Blotting, Western; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004731:Endotoxins / Q000633:toxicity; D005260:Female; D007275:Injections, Intravenous; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D019158:N-Acetylneuraminic Acid / Q000008:administration & dosage / Q000627:therapeutic use*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors*; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors*; D011506:Proteins / Q000037:antagonists & inhibitors; D034741:RNA, Small Interfering / Q000235:genetics; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors*
chemical_list: C545865:Atg5 protein, rat; D000071187:Autophagy-Related Protein 5; D004731:Endotoxins; D008562:Membrane Glycoproteins; D011506:Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; C044101:endotoxin, Escherichia coli; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D051571:Protein Kinase C-alpha; D019158:N-Acetylneuraminic Acid
keywords: apoptosis; autophagy; lipopolysaccharide; pyroptosis; reactive oxygen species; sialic acid; toll-like receptors