Abstract
Adiponectin is a multifunctional cytokine that has a role in regulating inflammation. Here we determined whether adiponectin modulates ischemic acute kidney injury. Compared with wild-type mice, adiponectin-knockout mice were found to have lower serum creatinine and less tubular damage or apoptosis following ischemia/reperfusion injury. This latter process was associated with decreased Bax and reduced activation of p53 and caspase-3. Targeted disruption of adiponectin was also found to inhibit the infiltration of neutrophils, macrophages, and T cells into the injured kidneys. This was associated with inhibition of NF-κB activation and reduced expression of the proinflammatory molecules IL-6, TNF-α, MCP-1, and MIP-2 in the kidney after ischemia/reperfusion injury. Wild-type mice engrafted with adiponectin-null bone marrow had less kidney dysfunction and tubular damage than adiponectin-null mice engrafted with wild-type bone marrow. Conversely, adiponectin-null mice engrafted with wild-type bone marrow had similar renal dysfunction and tubular damage compared with wild-type mice engrafted with wild-type bone marrow. In cultured macrophages, adiponectin directly promoted macrophage migration: a process blocked by the PI3 kinase inhibitor, LY294002. Thus, our results show that adiponectin has a pivotal role in the pathogenesis of acute renal ischemia/reperfusion injury and may be a potential therapeutic target.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute Kidney Injury / blood
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Acute Kidney Injury / genetics
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Acute Kidney Injury / immunology
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Acute Kidney Injury / pathology
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Acute Kidney Injury / prevention & control*
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Adiponectin / deficiency*
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Adiponectin / genetics
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Animals
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Apoptosis
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Bone Marrow Transplantation
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Caspase 3 / metabolism
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Chemokine CCL2 / metabolism
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Chemokine CXCL2 / metabolism
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Creatinine / blood
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Disease Models, Animal
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Enzyme Activation
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Inflammation Mediators / metabolism
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Interleukin-6 / metabolism
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Kidney / drug effects
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Kidney / immunology
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Kidney / metabolism*
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Kidney / pathology
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Macrophages / immunology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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NF-kappa B / metabolism
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Neutrophil Infiltration
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Phosphatidylinositol 3-Kinase / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors / pharmacology
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Reperfusion Injury / blood
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Reperfusion Injury / genetics
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Reperfusion Injury / immunology
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Reperfusion Injury / pathology
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Reperfusion Injury / prevention & control*
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T-Lymphocytes / immunology
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Tumor Necrosis Factor-alpha / metabolism
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Tumor Suppressor Protein p53 / metabolism
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bcl-2-Associated X Protein / metabolism
Substances
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Adiponectin
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Adipoq protein, mouse
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Bax protein, mouse
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Ccl2 protein, mouse
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Chemokine CCL2
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Chemokine CXCL2
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Cxcl2 protein, mouse
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Inflammation Mediators
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Interleukin-6
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NF-kappa B
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Tumor Necrosis Factor-alpha
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Tumor Suppressor Protein p53
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bcl-2-Associated X Protein
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Creatinine
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Phosphatidylinositol 3-Kinase
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Casp3 protein, mouse
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Caspase 3