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A novel eCIRP/TREM-1 pathway inhibitor attenuates acute kidney injury

  • Sara Siskind
    Affiliations
    Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY

    Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY

    Elmezzi Graduate School of Medicine, Manhasset, NY
    Search for articles by this author
  • William Royster
    Affiliations
    Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY

    Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY

    Elmezzi Graduate School of Medicine, Manhasset, NY
    Search for articles by this author
  • Max Brenner
    Affiliations
    Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY

    Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY

    Elmezzi Graduate School of Medicine, Manhasset, NY
    Search for articles by this author
  • Ping Wang
    Correspondence
    Reprint requests: Ping Wang, MD, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, 350 Community Dr, Manhasset, NY 11030.
    Affiliations
    Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY

    Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY

    Elmezzi Graduate School of Medicine, Manhasset, NY
    Search for articles by this author
Published:March 12, 2022DOI:https://doi.org/10.1016/j.surg.2022.02.003

      Abstract

      Background

      Extracellular cold-inducible RNA-binding protein aggravates acute kidney injury after renal ischemia/reperfusion. Although extracellular cold-inducible RNA-binding protein activates triggering receptor expressed on myeloid cells-1, how this receptor and its antagonism with a novel peptide M3 affects acute kidney injury is poorly understood. We, therefore, hypothesize that inhibiting the extracellular cold-inducible RNA-binding protein/triggering receptor expressed on myeloid cells-1 pathway with M3 attenuates acute kidney injury.

      Methods

      Wild-type and triggering receptor expressed on myeloid cells-1-/- mice were subjected to bilateral 30-minute renal hilum clamping followed by reperfusion or sham. After 4 hours, wild-type mice received M3 (10 mg/kg BW) or normal saline intraperitoneally. After 24 hours, renal tissue and serum were collected for analysis. Additionally, wild-type mice were subjected to bilateral renal ischemia for 34 minutes and treated with M3 at 10 mg/kg BW or vehicle at the time of reperfusion. Survival was monitored for 10 days.

      Results

      After renal ischemia/reperfusion, triggering receptor expressed on myeloid cells-1 messenger ribonucleic acid expression increased by 9-fold in wild-type mice compared to sham mice. Wild-type mice also demonstrated significant increases in serum blood urea nitrogen, creatinine, and interleukin-6 and renal tissue levels of interleukin-6 and neutrophil gelatinase-associated lipocalin after renal ischemia/reperfusion compared to sham mice. Triggering receptor expressed on myeloid cells-1-/- mice demonstrated significant reductions in serum blood urea nitrogen, creatinine, and interleukin-6 compared to wild-type mice after renal ischemia/reperfusion. Levels of renal interleukin-6 and neutrophil gelatinase-associated lipocalin were also significantly decreased in the kidneys of triggering receptor expressed on myeloid cells-1-/- mice. Furthermore, treatment with M3 in wild-type mice significantly decreased serum and renal levels of interleukin-6 after renal ischemia/reperfusion. M3 treatment demonstrated significant reductions in renal messenger ribonucleic acid and protein levels of neutrophil gelatinase-associated lipocalin, serum blood urea nitrogen and creatinine, and histologic structural damage as well as apoptosis. Treatment with M3 also increased survival from 35% to 65% in mice with acute kidney injury.

      Conclusion

      Triggering receptor expressed on myeloid cells-1 mediates the deleterious effects of extracellular cold-inducible RNA-binding protein in acute kidney injury after renal ischemia/reperfusion. The novel extracellular cold-inducible RNA-binding protein/triggering receptor expressed on myeloid cells-1 pathway antagonist, M3, attenuates acute kidney injury and has the potential to be developed as a therapeutic agent for acute kidney injury.
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