Background
Renal ischemia-reperfusion (RIR) injury, commonly caused by major surgery and shock, leads to acute kidney injury, and is associated with high morbidity and mortality. Cold-inducible RNA-binding protein (CIRP), a cold shock protein, has been recently identified as a damage-associated molecular pattern (DAMP). We hypothesized that CIRP exacerbates severity of injury in RIR.
Methods
Renal ischemia was induced in 8-week-old male C57BL/6 wild-type (WT) mice and Cirp−/− mice via bilateral clamping of renal pedicles for 30 min, followed by reperfusion for 5 h or 24 h and harvest of blood and renal tissue for analysis. Anti-CIRP antibody or non-immunized IgG was injected intravenously (10 mg/kg body weight) at time of reperfusion.
Results
After RIR, Cirp−/− mice demonstrated a reduction of BUN and creatinine of 53% and 60%, respectively, compared to WT mice. Serum IL-6 levels were significantly reduced 70% in Cirp−/− mice compared to WT mice after RIR. Levels of nitrotyrosine, an oxidatively-modified protein marker, and cyclooxygenase-2, an inflammatory mediator, were also significantly decreased in the kidneys of the Cirp−/− mice compared to WT mice after RIR. Renal caspase-3 activity was decreased in Cirp−/− mice compared to WT mice after RIR, which corresponded to the reduction of apoptotic cells determined by TUNEL assay. Injection of neutralizing anti-CIRP antibody into WT mice led to an 82% reduction in BUN compared to the vehicle after RIR.
Conclusions
Deficiency of CIRP results in less renal injury after RIR by attenuating inflammation and oxidative stress. Furthermore, blockade of CIRP shows a protective effect, indicating CIRP as a target in the treatment of RIR.