Thermoneutral Regulation and Acute Injury: Implications for Acute Kidney Injury.

Acute kidney injury (AKI) has demonstrated sex differences as illustrated in clinical and preclinical studies. In most cases, females show a significant resistance to AKI as manifested by renal indicators of injury, and thus much of the literature is derived from studies exclusively in males. Thermoneutral housing alters sex differences in acute injury of the liver, but has not been studied in the kidney. Thermoneutrality, the ambient temperature at which additional energy is not needed to maintain core body temperature, is regulated by mechanisms residing in mitochondria. Importantly, mitochondrial function plays an important role in induction and recovery of AKI. Mechanisms that regulate thermoneutrality include uncoupling proteins (UCPs) and one of its upstream regulators peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). PGC-1α has been extensively studied in AKI in males. UCP-2, a UCP expressed in the kidney, has been minimally studied in AKI in males. Expression of other UCPs in the kidney has not been well defined. No studies of either PGC-1α or UCPs have interrogated for a sex difference nor have they been investigated at thermoneutrality in the kidney. In this brief review, pathways of importance in thermoneutrality are described and related to pathways of importance in modulating susceptibility to AKI. Clarity in the understanding of the impact of thermoneutrality on AKI in altering susceptibility in females may expand our understanding of the critical role of mitochondrial function in this setting. Unique utilization of mitochondrial-based molecular pathways in females may then inform potential therapies.