Renal Protection From Prolonged Cold Ischemia and Warm Reperfusion in Hibernating Squirrels

Background. We have previously shown that cold ischemia (CI) results in massive increases in caspase-3 activity, tubular apoptosis, and brush border injury (BBI) in mouse kidneys. During hibernation, the 13-lined ground squirrel (GS) cycles through repeated CI during torpor, followed by warm ischemia/reperfusion (WI) during interbout arousal (IBA). We sought to determine whether CI and WI during hibernation caused caspase-3 activation, tubular apoptosis, acute tubular necrosis, or BBI, and reduced renal function. We also determined whether protection was dependent on the stage of hibernation. Methods. Radiotelemeters were implanted in 1-year-old GS, and core body temperature was remotely monitored. GS kidneys at various stages of hibernation were subjected to ex vivo CI. Results. Tubular apoptosis was not detected and caspase-3-like activity was not different between hibernating and summer kidneys. Despite prolonged CI followed by WI and reperfusion, acute tubular necrosis and apoptosis did not occur in hibernating kidneys. BBI was absent in torpid kidneys but significantly increased in IBA kidneys and associated with an increase in caspase-3-like activity, suggesting that IBA kidneys are more susceptible to injury than summer or torpid kidneys. Renal function and urine concentrating ability diminished during torpor but returned during IBA. Conclusions. Despite BBI, IBA kidneys clear serum creatinine and concentrate urine. Kidneys from both summer and hibernating animals tolerated ex vivo CI, confirming that protection from apoptotic and necrotic cell death is independent of the stage of hibernation. An understanding of how renal protection occurs during hibernation may help in understanding the pathophysiology of delayed graft function.