Cindy Cen1, Weng-Lang Yang2, Hao-Ting Yen3, Jeffrey M Nicastro1, Gene F Coppa1, Ping Wang4. 1. Department of Surgery, Hofstra Northwell School of Medicine, Manhasset, NY. 2. Department of Surgery, Hofstra Northwell School of Medicine, Manhasset, NY; Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, NY. 3. Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, NY. 4. Department of Surgery, Hofstra Northwell School of Medicine, Manhasset, NY; Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, NY. Electronic address: pwang@northwell.edu.
Abstract
BACKGROUND: Renal ischemia-reperfusion injury, commonly caused by major operation and shock, leads to acute kidney injury and is associated with high morbidity and mortality. Cold-inducible ribonucleic acid-binding protein, a cold shock protein, has recently been identified as a damage-associated molecular pattern. We hypothesized that cold-inducible ribonucleic acid-binding protein exacerbates severity of injury in renal ischemia-reperfusion. METHODS: Renal ischemia was induced in an 8-week-old male C57BL/6 wild-type mice and Cirp(-/-) mice via bilateral clamping of renal pedicles for 30 minutes, followed by reperfusion for 5 or 24 hours and harvest of blood and renal tissue for analysis. Anti-cold-inducible ribonucleic acid-binding protein antibody or non-immunized immunoglobulin G (IgG) was injected intravenously (10 mg/kg body weight) at time of reperfusion. RESULTS: After renal ischemia-reperfusion, Cirp(-/-) mice demonstrated a reduction of blood urea nitrogen and creatinine of 53% and 60%, respectively, compared with wild-type mice. Serum IL-6 levels were reduced significantly: 70% in Cirp(-/-) mice compared with wild-type mice after renal ischemia-reperfusion. Levels of nitrotyrosine, an oxidatively modified protein marker, and cyclooxygenase-2, an inflammatory mediator, also were significantly decreased in the kidneys of the Cirp(-/-) mice compared with wild-type mice after renal ischemia-reperfusion. Renal caspase-3 activity was decreased in Cirp(-/-) mice compared with wild-type mice after renal ischemia-reperfusion, which corresponded to the reduction of apoptotic cells determined by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Injection of neutralizing anti-cold-inducible ribonucleic acid-binding protein antibody into wild-type mice led to an 82% reduction in blood urea nitrogen compared with the vehicle after renal ischemia-reperfusion. CONCLUSION: Deficiency of cold-inducible ribonucleic acid-binding protein results in less renal injury after renal ischemia-reperfusion by attenuating inflammation and oxidative stress. Furthermore, blockade of cold-inducible ribonucleic acid-binding protein shows a protective effect, indicating cold-inducible ribonucleic acid-binding protein as a target in the treatment of renal ischemia-reperfusion.
BACKGROUND: Renal ischemia-reperfusion injury, commonly caused by major operation and shock, leads to acute kidney injury and is associated with high morbidity and mortality. Cold-inducible ribonucleic acid-binding protein, a cold shock protein, has recently been identified as a damage-associated molecular pattern. We hypothesized that cold-inducible ribonucleic acid-binding protein exacerbates severity of injury in renal ischemia-reperfusion. METHODS:Renal ischemia was induced in an 8-week-old male C57BL/6 wild-type mice and Cirp(-/-) mice via bilateral clamping of renal pedicles for 30 minutes, followed by reperfusion for 5 or 24 hours and harvest of blood and renal tissue for analysis. Anti-cold-inducible ribonucleic acid-binding protein antibody or non-immunized immunoglobulin G (IgG) was injected intravenously (10 mg/kg body weight) at time of reperfusion. RESULTS: After renal ischemia-reperfusion, Cirp(-/-) mice demonstrated a reduction of blood ureanitrogen and creatinine of 53% and 60%, respectively, compared with wild-type mice. Serum IL-6 levels were reduced significantly: 70% in Cirp(-/-) mice compared with wild-type mice after renal ischemia-reperfusion. Levels of nitrotyrosine, an oxidatively modified protein marker, and cyclooxygenase-2, an inflammatory mediator, also were significantly decreased in the kidneys of the Cirp(-/-) mice compared with wild-type mice after renal ischemia-reperfusion. Renal caspase-3 activity was decreased in Cirp(-/-) mice compared with wild-type mice after renal ischemia-reperfusion, which corresponded to the reduction of apoptotic cells determined by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Injection of neutralizing anti-cold-inducible ribonucleic acid-binding protein antibody into wild-type mice led to an 82% reduction in blood ureanitrogen compared with the vehicle after renal ischemia-reperfusion. CONCLUSION: Deficiency of cold-inducible ribonucleic acid-binding protein results in less renal injury after renal ischemia-reperfusion by attenuating inflammation and oxidative stress. Furthermore, blockade of cold-inducible ribonucleic acid-binding protein shows a protective effect, indicating cold-inducible ribonucleic acid-binding protein as a target in the treatment of renal ischemia-reperfusion.
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