Abstract
Interleukin (IL)-18 is produced by leukocytes and renal parenchymal cells (tubular epithelial cells, podocytes, and mesangial cells). The IL-18 receptor (IL-18R) is expressed on these cells in cisplatin-induced acute kidney injury, but the role of IL-18R is unknown. To help define this, we compared IL-18Rα knockout with wild-type mice in cisplatin-induced acute kidney injury and found deteriorated kidney function, tubular damage, increased accumulation of leukocytes (CD4(+) and CD8(+) T-cells, macrophages, and neutrophils), upregulation of early kidney injury biomarkers (serum TNF, urinary IL-18, and KIM-1 levels), and increased expression of pro-inflammatory molecules downstream of IL-18. In vitro, leukocytes from the spleen and kidneys of the knockout mice produced greater amounts of pro-inflammatory cytokines upon stimulation with concanavalin A compared to that in wild-type mice. Levels of the suppressor of cytokine signaling 1 and 3 (negative regulators of cytokine signaling) were reduced in the spleen and kidneys of IL-18Rα-deficient compared to wild-type mice. Adoptive transfer of wild-type splenocytes by IL-18Rα-deficient mice led to decreased cisplatin nephrotoxicity compared to control IL-18Rα-deficient mice. In contrast, anti-IL-18Rα and anti-IL-18Rβ antibody treatment tended to increase cisplatin nephrotoxicity in wild-type mice. Thus, signaling through IL-18Rα activates both inflammation-suppressing and pro-injury pathways in cisplatin-induced acute kidney injury.
MeSH terms
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Acute Kidney Injury / chemically induced
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Acute Kidney Injury / immunology*
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Acute Kidney Injury / pathology*
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Acute Kidney Injury / physiopathology
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Adoptive Transfer
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Animals
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Antibodies, Blocking / administration & dosage
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Apoptosis
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Base Sequence
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Biomarkers / metabolism
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Caspase 3 / metabolism
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Chemokines / biosynthesis
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Chemokines / genetics
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Cisplatin / toxicity
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Cytokines / biosynthesis
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Cytokines / genetics
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Hepatitis A Virus Cellular Receptor 1
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Inflammation / immunology
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Inflammation / prevention & control
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Interleukin-18 / blood
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Interleukin-18 / urine
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Interleukin-18 Receptor alpha Subunit / antagonists & inhibitors
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Interleukin-18 Receptor alpha Subunit / deficiency
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Interleukin-18 Receptor alpha Subunit / genetics
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Interleukin-18 Receptor alpha Subunit / metabolism*
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Lymphocyte Activation
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Macrophages / pathology
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Male
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Membrane Proteins / metabolism
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Membrane Proteins / urine
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Neutrophils / pathology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Signal Transduction / immunology
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins / genetics
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Suppressor of Cytokine Signaling Proteins / metabolism
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T-Lymphocyte Subsets / pathology
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Transcription Factor RelA / metabolism
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Tumor Necrosis Factor-alpha / blood
Substances
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Antibodies, Blocking
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Biomarkers
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Chemokines
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Cytokines
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Havcr1 protein, mouse
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Hepatitis A Virus Cellular Receptor 1
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Il18r1 protein, mouse
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Interleukin-18
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Interleukin-18 Receptor alpha Subunit
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Membrane Proteins
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RNA, Messenger
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Rela protein, mouse
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Socs1 protein, mouse
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Socs3 protein, mouse
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Transcription Factor RelA
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Tumor Necrosis Factor-alpha
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Casp3 protein, mouse
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Caspase 3
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Cisplatin