Caspase-1-Inhibitor AC-YVAD-CMK Inhibits Pyroptosis and Ameliorates Acute Kidney Injury in a Model of Sepsis

Overview

Journal Biomed Res Int

Publisher Wiley

Specialties Biomedical Engineering
Biotechnology
General Medicine

Date 2021 Jul 5

PMID 34222479

Citations 17

Authors

Mei Yang

Jin-Tao Fang

Ni-Shang Zhang

Long-Jiang Qin

Yang-Yang Zhuang

Wei-Wei Wang

Hai-Ping Zhu

Yan-Jie Zhang

Peng Xia

Yan Zhang

Affiliations

Soon will be listed here.

Abstract

Objective: To observe the protective effect of AC-YVAD-CMK on sepsis-induced acute kidney injury in mice and to explore its possible mechanisms primarily.

Methods: Eighteen male C57BL/6 mice were randomly divided into sham-operated group (Control), cecal ligation and puncture group (CLP), and CLP model treated with AC-YVAD-CMK group (AC-YVAD-CMK) ( = 6 in each group). Mice were sacrificed at 24 h after operation, and blood and kidney tissue samples were collected for analyses. Histologic changes were determined microscopically following HE staining. The expression of Ly-6B and CD68 was investigated using immunohistochemistry. Serum concentrations of creatinine (sCR) and blood urea nitrogen (BUN) were measured. Serum levels of interleukin-1 (IL-1), interleukin-18 (IL-18), TNF-, and interleukin-6 (IL-6) were determined by ELISA. The expressions of Caspas-1, NLRP-1, IL-1, and IL-18 in renal tissues were investigated using Western blot. Immunofluorescence staining was used to detect the expression of GSDMD protein in renal tissues.

Results: AC-YVAD-CMK treatment significantly alleviates sepsis-induced acute kidney injury, with decreased histological injury in renal tissues, suppresses the accumulation of neutrophils and macrophages in renal tissues, and decreased sCR and BUN level ( < 0.05). Attenuation of sepsis-induced acute kidney injury was due to the prohibited production of inflammatory cytokines and decrease expression of Caspas-1, NLRP-1, IL-1, and IL-18 in renal tissues. In addition, AC-YVAD-CMK treatment significantly reduced the expression of GSDMD in renal tissues compared to those observed in controls ( < 0.05).

Conclusions: We demonstrated a marked renoprotective effect of caspase-1-inhibitor AC-YVAD-CMK in a rat model of sepsis by inhibition of pyroptosis.

Citing Articles

Inflammasomes and idiopathic inflammatory myopathies.

Sun R, Chu J, Li P Front Immunol. 2024; 15:1449969.

PMID: 39723212 PMC: 11668653. DOI: 10.3389/fimmu.2024.1449969.

Immunoadjuvant therapy in the regulation of cell death in sepsis: recent advances and future directions.

Islam M, Watanabe E, Salma U, Ozaki M, Irahara T, Tanabe S Front Immunol. 2024; 15:1493214.

PMID: 39720718 PMC: 11666431. DOI: 10.3389/fimmu.2024.1493214.

IL-18 biology in severe asthma.

Thawanaphong S, Nair A, Volfson E, Nair P, Mukherjee M Front Med (Lausanne). 2024; 11:1486780.

PMID: 39554494 PMC: 11566457. DOI: 10.3389/fmed.2024.1486780.

Beyond Inflammation: Role of Pyroptosis Pathway Activation by Gram-Negative Bacteria and Their Outer Membrane Vesicles (OMVs) in the Interaction with the Host Cell.

Resta S, Guerra F, Tala A, Bucci C, Alifano P Cells. 2024; 13(21.

PMID: 39513865 PMC: 11545737. DOI: 10.3390/cells13211758.

Taking AIM at Influenza: The Role of the AIM2 Inflammasome.

Xu D, Tate M Viruses. 2024; 16(10).

PMID: 39459869 PMC: 11512208. DOI: 10.3390/v16101535.

References

Silverman W, de Rivero Vaccari J, Locovei S, Qiu F, Carlsson S, Scemes E . The pannexin 1 channel activates the inflammasome in neurons and astrocytes. J Biol Chem. 2009; 284(27):18143-51. PMC: 2709345. DOI: 10.1074/jbc.M109.004804. View

Schroder K, Tschopp J . The inflammasomes. Cell. 2010; 140(6):821-32. DOI: 10.1016/j.cell.2010.01.040. View

Linkermann A, Chen G, Dong G, Kunzendorf U, Krautwald S, Dong Z . Regulated cell death in AKI. J Am Soc Nephrol. 2014; 25(12):2689-701. PMC: 4243360. DOI: 10.1681/ASN.2014030262. View

Wu D, Pan P, Liu B, Su X, Zhang L, Tan H . Inhibition of Alveolar Macrophage Pyroptosis Reduces Lipopolysaccharide-induced Acute Lung Injury in Mice. Chin Med J (Engl). 2015; 128(19):2638-45. PMC: 4736856. DOI: 10.4103/0366-6999.166039. View

Shao B, Xu Z, Han B, Su D, Liu C . NLRP3 inflammasome and its inhibitors: a review. Front Pharmacol. 2015; 6:262. PMC: 4633676. DOI: 10.3389/fphar.2015.00262. View

Bergsbaken T, Fink S, Cookson B . Pyroptosis: host cell death and inflammation. Nat Rev Microbiol. 2009; 7(2):99-109. PMC: 2910423. DOI: 10.1038/nrmicro2070. View

Krautwald S, Linkermann A . The fire within: pyroptosis in the kidney. Am J Physiol Renal Physiol. 2013; 306(2):F168-9. DOI: 10.1152/ajprenal.00552.2013. View

Yang J, Yao F, Zhang J, Ji Z, Li K, Zhan J . Ischemia-reperfusion induces renal tubule pyroptosis via the CHOP-caspase-11 pathway. Am J Physiol Renal Physiol. 2013; 306(1):F75-84. DOI: 10.1152/ajprenal.00117.2013. View

Conforti-Andreoni C, Ricciardi-Castagnoli P, Mortellaro A . The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond. Cell Mol Immunol. 2011; 8(2):135-45. PMC: 4003142. DOI: 10.1038/cmi.2010.81. View

10.

Yang M, Zhuang Y, Wang W, Zhu H, Zhang Y, Zheng S . Role of Sirolimus in renal tubular apoptosis in response to unilateral ureteral obstruction. Int J Med Sci. 2018; 15(13):1433-1442. PMC: 6216060. DOI: 10.7150/ijms.26954. View

11.

Timoshanko J, Kitching A, Iwakura Y, Holdsworth S, Tipping P . Leukocyte-derived interleukin-1beta interacts with renal interleukin-1 receptor I to promote renal tumor necrosis factor and glomerular injury in murine crescentic glomerulonephritis. Am J Pathol. 2004; 164(6):1967-77. PMC: 1615771. DOI: 10.1016/s0002-9440(10)63757-1. View

12.

Kaushal G, Basnakian A, Shah S . Apoptotic pathways in ischemic acute renal failure. Kidney Int. 2004; 66(2):500-6. DOI: 10.1111/j.1523-1755.2004.761_6.x. View

13.

Thomasova D, Bruns H, Kretschmer V, Ebrahim M, Romoli S, Liapis H . Murine Double Minute-2 Prevents p53-Overactivation-Related Cell Death (Podoptosis) of Podocytes. J Am Soc Nephrol. 2014; 26(7):1513-23. PMC: 4483582. DOI: 10.1681/ASN.2014040345. View

14.

Masters S, Gerlic M, Metcalf D, Preston S, Pellegrini M, ODonnell J . NLRP1 inflammasome activation induces pyroptosis of hematopoietic progenitor cells. Immunity. 2012; 37(6):1009-23. PMC: 4275304. DOI: 10.1016/j.immuni.2012.08.027. View

15.

Bagshaw S, George C, Bellomo R . Early acute kidney injury and sepsis: a multicentre evaluation. Crit Care. 2008; 12(2):R47. PMC: 2447598. DOI: 10.1186/cc6863. View

16.

Rabb H . Immune modulation of acute kidney injury. J Am Soc Nephrol. 2006; 17(3):604-6. DOI: 10.1681/ASN.2006010060. View

17.

Srisawat N, Lawsin L, Uchino S, Bellomo R, Kellum J . Cost of acute renal replacement therapy in the intensive care unit: results from The Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) study. Crit Care. 2010; 14(2):R46. PMC: 2887158. DOI: 10.1186/cc8933. View

18.

Lichtnekert J, Kulkarni O, Mulay S, Rupanagudi K, Ryu M, Allam R . Anti-GBM glomerulonephritis involves IL-1 but is independent of NLRP3/ASC inflammasome-mediated activation of caspase-1. PLoS One. 2011; 6(10):e26778. PMC: 3203143. DOI: 10.1371/journal.pone.0026778. View

19.

Wu H, Huang T, Ying L, Han C, Li D, Xu Y . MiR-155 is Involved in Renal Ischemia-Reperfusion Injury via Direct Targeting of FoxO3a and Regulating Renal Tubular Cell Pyroptosis. Cell Physiol Biochem. 2016; 40(6):1692-1705. DOI: 10.1159/000453218. View

20.

Lorenz G, Darisipudi M, Anders H . Canonical and non-canonical effects of the NLRP3 inflammasome in kidney inflammation and fibrosis. Nephrol Dial Transplant. 2013; 29(1):41-8. DOI: 10.1093/ndt/gft332. View