Synchronization of the 12-hour circatidal rhythm maintains the kidney through repeated cycles of warm reperfusion in the hibernating ground squirrel

The hibernating 13-lined ground squirrel kidney is a unique natural model of resistance to damage caused by cold storage and warm reperfusion. Over months, the kidney is exposed to cycles between multi-day periods of torpor with low perfusion at ice-cold temperature, and rapid warm reperfusion during arousals. Serum creatinine accumulates during torpor but normalizes during arousal and animals emerge each spring with functioning kidneys. After confirming a lack of kidney histopathology in sections from 11 animals that had completed 11-22 torpor-arousal cycles, we collected RNA-seq data from 32 ground squirrel kidneys representing six key transitional timepoints based on seasonal and torpor-arousal cycle physiology. Hibernation state-specific gene expression changes were identified after removing three informative outliers. Both seasonal and torpor-arousal cycle-specific gene expression changes were found. These differentially-expressed genes illuminated molecular mechanisms that mitigate damage whilst supporting full recovery during each ∼12h rewarming. As with the response to renal ischemia-reperfusion injury in other species, the arousing hibernator induced immediate early genes during warm reperfusion. But, in the hibernator, this response did not precipitate the gene expression program of maladaptive repair that is characterized by cell death, immune system activation and fibrosis. Rather it appears that induction of immediate early genes activated a universal 12-hour, ‘circatidal’ rhythm. The efficient unfolding of this rhythm across each arousal from torpor was facilitated by the seasonally-changed background primed for rapid cell division and minimal energy consumption. Adaptive repair was achieved, with proteostasis and cell-type specific function restored, assuring that minor damage did not accumulate.