S-Nitrosoglutathione protects acute kidney injury in septic rats by inhibiting the activation of NLRP3 inflammasome

Document Type : Original Article


Department of Intensive Care Unit, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang Province, P.R China


Objective(s): We aimed to study the effect of S-nitroso glutathione (SNG) on acute kidney injury (AKI) in septic rats by regulating nucleotide oligomerization domain-like receptor protein 3 (NLRP3).
Materials and Methods: Sprague Dawley rats were used to construct the AKI model, and biochemical methods were used to detect the levels of inflammatory factors and anti-oxidant enzymes in renal tissue. We observed the ultrastructural changes of renal tissue by transmission electron microscopy and detected the protein and mRNA levels of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain foci (ASC) and Caspase-1 by western-blotting and RT-qPCR. 
Results: Cecal ligation and puncture induced renal tubular epithelial tissue damage in septic rats, resulting in decreased renal function, increased levels of inflammation and decreased levels of anti-oxidant enzymes in renal tissue, and aggravated mitochondrial damage, significantly decreased mitochondrial density and enzyme complex I/II/III/IV levels (all P<0.001), and increased the protein and mRNA expression of NLRP3, ASC, and Caspase-1 (all P<0.001). However, after pretreatment with SNG, the pathological damage of renal tubular epithelial tissue was reduced, the renal function was improved, the level of inflammation in renal tissue decreased and the level of anti-oxidant enzymes increased, the density of mitochondria and the level of enzyme complex I/II/III/IV were significantly increased (all P<0.001), meanwhile the protein and mRNA levels of NLRP3, ASC, and Caspase-1 were all decreased significantly (all P<0.05).
Conclusion: SNG protects AKI in septic rats by inhibiting NLRP3 inflammasome activation. 


Main Subjects

1. Cecconi M, Evans L, Levy M, Rhodes A. Sepsis and septic shock. Lancet 2018;392:75-87.
2. Dugar S, Choudhary C, Duggal A. Sepsis and septic shock: Guideline-based management. Cleve Clin J Med 2020;87:53-64.
3. Chiu C, Legrand M. Epidemiology of sepsis and septic shock. Curr Opin Anaesthesiol 2021;34:71-76.
4. Peerapornratana S, Manrique-Caballero CL, Gómez H, Kellum JA. Acute kidney injury from sepsis: current concepts, epidemiology, pathophysiology, prevention and treatment. Kidney Int 2019;96:1083-1099. 
5. Manrique-Caballero CL, Del Rio-Pertuz G, Gomez H. Sepsis-Associated Acute Kidney Injury. Crit Care Clin 2021;37:279-301.
6. Yao Y, Hu X, Feng X, Zhao Y, Song M, Wang C, et al. Dexmedetomidine alleviates lipopolysaccharide-induced acute kidney injury by inhibiting the NLRP3 inflammasome activation via regulating the TLR4/NOX4/NF-κB pathway. J Cell Biochem 2019;120:18509-18523. 
7. Fan H, Zhao Y, Zhu JH. S-Nitrosoglutathione protects lipopolysaccharide-induced acute kidney injury by inhibiting toll-like receptor 4-nuclear factor-κB signal pathway. J Pharm Pharmacol 2019;71:1255-1261.
8. Fan H, Le JW, Sun M, Zhu JH. Pretreatment with S-Nitrosoglutathione attenuates septic acute kidney injury in rats by inhibiting inflammation, oxidation, and apoptosis. Biomed Res Int 2021;2021:6678165. 
9. Kalantari K, Rosner MH. Recent advances in the pharmacological management of sepsis-associated acute kidney injury. Expert Rev Clin Pharmacol 2021;14:1401-1411.
10. Fani F, Regolisti G, Delsante M, Cantaluppi V, Castellano G, Gesualdo L, et al. Recent advances in the pathogenetic mechanisms of sepsis-associated acute kidney injury. J Nephrol 2018;31:351-359. 
11. Rello J, Valenzuela-Sánchez F, Ruiz-Rodriguez M, Moyano S. Sepsis: A review of advances in management. Adv Ther 2017;34:2393-2411.
12. Petejova N, Martinek A, Zadrazil J, Kanova M, Klementa V, Sigutova R, et al. Acute kidney injury in septic patients treated by selected nephrotoxic antibiotic agents-pathophysiology and biomarkers-a review. Int J Mol Sci 2020;21:7115.
13. Fan H, Le JW, Sun M, Zhu JH. Sirtuin 3 deficiency promotes acute kidney injury induced by sepsis via mitochondrial dysfunction and apoptosis. Iran J Basic Med Sci 2021;24:675-681.
14. Huang G, Bao J, Shao X, Zhou W, Wu B, Ni Z, et al. Inhibiting pannexin-1 alleviates sepsis-induced acute kidney injury via decreasing NLRP3 inflammasome activation and cell apoptosis. Life Sci 2020;254:117791.
15. Wang Y, Zhu J, Liu Z, Shu S, Fu Y, Liu Y, et al. The PINK1/PARK2/optineurin pathway of mitophagy is activated for protection in septic acute kidney injury. Redox Biol 2021;38:101767. 
16. Yu H, Jin F, Liu D, Shu G, Wang X, Qi J, et al. ROS-responsive nano-drug delivery system combining mitochondria-targeting ceria nanoparticles with atorvastatin for acute kidney injury. Theranostics 2020;10:2342-2357. 
17. Wang K, Xie S, Xiao K, Yan P, He W, Xie L. Biomarkers of sepsis-induced acute kidney injury. Biomed Res Int 2018;2018:6937947.
18. Fan H, Su BJ, Le JW, Zhu JH. Salidroside protects acute kidney injury in septic rats by inhibiting inflammation and apoptosis. Drug Des Devel Ther 2022;16:899-907. 
19. Chen Y, Jin S, Teng X, Hu Z, Zhang Z, Qiu X, et al. Hydrogen sulfide attenuates LPS-induced acute kidney injury by inhibiting inflammation and oxidative stress. Oxid Med Cell Longev 2018;2018:6717212.
20. Yang J, Miao X, Guan Y, Chen C, Chen S, Zhang X, et al. Microbubble functionalization with platelet membrane enables targeting and early detection of sepsis-induced acute kidney injury. Adv Healthc Mater 2021;10:e2101628.
21. Wang ZF, Yang YM, Fan H. Protective effect of S-Nitrosoglutathione pretreatment on acute lung injury in septic rats. Iran J Basic Med Sci 2020;23:1059-1064. 
22. Hu Q, Ren J, Ren H, Wu J, Wu X, Liu S, et al. Urinary mitochondrial DNA identifies renal dysfunction and mitochondrial damage in sepsis-induced acute kidney injury. Oxid Med Cell Longev 2018;2018:8074936.
23. Gao Y, Dai X, Li Y, Li G, Lin X, Ai C, et al. Role of Parkin-mediated mitophagy in the protective effect of polydatin in sepsis-induced acute kidney injury. J Transl Med 2020;18:114-126. 
24. Wang QL, Xing W, Yu C, Gao M, Deng LT. ROCK1 regulates sepsis-induced acute kidney injury via TLR2-mediated endoplasmic reticulum stress/pyroptosis axis. Mol Immunol 2021;138:99-109.
25. Ye Z, Zhang L, Li R, Dong W, Liu S, Li Z, et al. Caspase-11 mediates pyroptosis of tubular epithelial cells and septic acute kidney injury. Kidney Blood Press Res 2019;44:465-478.
26. Tanuseputero SA, Lin MT, Yeh SL, Yeh CL. Intravenous arginine administration downregulates NLRP3 inflammasome activity and attenuates acute kidney injury in mice with polymicrobial sepsis. Mediators Inflamm 2020;2020:3201635.
27. Juan CX, Mao Y, Cao Q, Chen Y, Zhou LB, Li S, et al. Exosome-mediated pyroptosis of miR-93-TXNIP-NLRP3 leads to functional difference between M1 and M2 macrophages in sepsis-induced acute kidney injury. J Cell Mol Med 2021;25:4786-4799.