ABSTRACT
Acute kidney injury (AKI) is characterized by mitochondrial dysfunction and activation of the innate immune system. The cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) pathway detects cytosolic DNA and induces innate immunity. Here, we investigate the role of mitochondrial damage and subsequent activation of the cGAS-STING pathway using a genetically engineered animal model of cisplatin-induced AKI and cultured tubular cells. Cisplatin induced mtDNA leakage into the cytosol-probably through BCL-2-like protein 4 (BAX) pores in the mitochondrial outer membrane-in tubules, with subsequent activation of the cGAS-STING pathway, thereby triggering inflammation and AKI progression, which is improved in STING-deficient mice. STING knockdown in cultured tubular cells ameliorates inflammatory responses induced by cisplatin. mtDNA depletion and repletion studies support tubular inflammatory responses via the cGAS-STING signal activation by cytosolic mtDNA. Therefore, we conclude that mitochondrial dysfunction and subsequent activation of the mtDNA-cGAS-STING pathway is a critical regulator of kidney injury.
Subject(s)
Acute Kidney Injury/metabolism , Acute Kidney Injury/pathology , Inflammation/pathology , Membrane Proteins/metabolism , Mitochondria/pathology , Nucleotidyltransferases/metabolism , Acute Kidney Injury/chemically induced , Animals , Cell Line , Cell Movement/drug effects , Cisplatin/adverse effects , Cytosol/metabolism , DNA, Mitochondrial/metabolism , Humans , Kidney Tubules/drug effects , Kidney Tubules/pathology , Male , Mice, Inbred C57BL , Mitochondria/drug effects , Mitochondria/metabolism , Neutrophils/drug effects , Neutrophils/metabolism , Signal Transduction/drug effects , bcl-2-Associated X Protein/metabolismABSTRACT
ABO-incompatible blood transfusion is potentially a life-threatening event. A 74-year-old type O Rh-positive male was accidentally transfused with 280 mL type B Rh-positive red blood cells during open right hemicolectomy, causing ABO-incompatible blood transfusion. Immediately after the transfusion, the patient experienced a hypotension episode followed by acute hemolytic reaction, disseminated intravascular coagulation and acute kidney injury. Plasma exchange therapy was performed to remove anti-B antibody and free hemoglobin because they caused acute hemolytic reaction, disseminated intravascular coagulation, and acute kidney injury. Free hemoglobin levels decreased from 13 to 2 mg/dL for 2 h. Continuous hemodiafiltration was used to stabilize hemodynamics. The patient was successfully treated for acute hemolytic reaction, disseminated intravascular coagulation, and acute kidney injury. Plasma exchange therapy and continuous hemodiafiltration are likely to be effective treatments for ABO-incompatible blood transfusion, and further studies are required to assess this effectiveness in future.
