Synchronization of the 12-h 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 multiday 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 sequencing (RNA-Seq) data from 32 ground squirrel kidneys representing 6 key transitional time points 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 while supporting full recovery during each ∼12 h 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-h, "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.NEW & NOTEWORTHY The hibernator kidney exhibits no damage after 10-22 cycles between prolonged cold exposure and rapid warm reperfusion occurring over several months. As found with kidney damage in other species, each rewarming activates an immediate early gene response. Unique to the hibernator, adaptive repair is completed within 12 h, facilitated by rapid activation of the universal "circatidal" rhythm unfolding on a seasonally primed background that assures minimal cell death, rapid cell division, and repair.