Hibernating Bears (Ursidae)

Metabolic Magicians of Definite Interest for the Nephrologist

Peter Stenvinkel; Alkesh H Jani; Richard J Johnson

Disclosures

Kidney Int. 2013;83(2):207-212. 

In This Article

Marked Reduction In GFR Yet Minimal Azotemia During Hibernation

In 1971, Brown et al.[11] demonstrated that hibernating bears decrease their GFR by about 70% and become anuric because of the complete reabsorption of the kidney filtrate and the urinary bladder (the latter which absorbs about 100 ml every 24 h).[12] In another study of the Romanian brown bear, it was reported that glomeruli are partially sclerosed in early spring.[13] Despite the fact that GFR is depressed in hibernating bears, blood urea nitrogen does not rise but rather remains constant or decreases during hibernation, reaching levels of ~5–10 mg/dl.[5,14] The reason why azotemia does not develop in hibernating bears is because of both decreased urea generation and because the urea that is generated is rapidly recycled into protein.[15] The decrease in urea production is due to the fact that urea is in essence a product of protein metabolism, and during hibernation the bear is primarily metabolizing fat. Some urea is always produced during normal cell metabolism, but in the bear it is recycled back into protein. The mechanism(s) are not completely clear, but has been postulated to result from the passage of urea into the intestine, where it is hydrolyzed by urease-expressing gut bacteria to release ammonia.[8,12,16] Although some of the ammonia may be used by the gut bacteria for their own growth,[17] other ammonia is absorbed where it can react with glycerol released during the lipolysis of fat to make amino acids. It has been postulated that in hibernating bears a reduction in metabolic activity of the gut flora is an integral part of the adaptation to metabolic stability.[18] Nelson[19] showed that urea is recycled and resynthesized into skeletal muscle and other body proteins in hibernating bears, thereby preserving lean body mass. Thus, waste products of plasma nitrogen are lower in brown bears during winter sleep compared with before hibernation.[20] A novel mechanism by which urea cycling is regulated may be via the activation of the mammalian mitochondrial sirtuin (nicotinamide adenine dinucleotide-dependent protein deacetylases). Nakagawa et al.[21] reported that SIRT5 regulates the urea cycle via deacetylation of carbamoyl phosphate synthetase 1, which is a rate-limiting step in the urea cycle and has a pivotal role in ammonia detoxification. Thus, as SIRT5-deficient mice have 30% lower carbamoyl phosphate synthetase 1 activity and showed hyperammonemia during fasting,[21] studies should test whether sirtuin activity is upregulated by dietary shifts, such as increased intake of Vaccinum berries (i.e., blueberry, lingonberry, etc.) before hibernation. It has been speculated that sirtuins have an important role in the transcriptional control of important metabolic pathways in hibernators.[22]

The ability of bears to recycle urea is related to a specific adaptation that occurs during hibernation. Interestingly, urea recycling is not completely tied to the fall in temperature associated with hibernation, as it can occur shortly before the temperature decreases,[23] and can extend for 7–10 days following arousal.[15] It is tied closely to a period when the bear obtains its entire energy from fat. Indeed, Nelson[12] showed that during the summer bears will respond appropriately to fasting or dehydration with a rise in blood urea nitrogen. In a metabolic study with 125I-labeled serum albumin and 14C-labeled leucine in four male black bears, Lundberg et al.[24] showed that more leucine was incorporated in plasma proteins during hibernation than in the active state. In another study, Lohuis et al.[25] used 14C-phenylalanine as a tracer to demonstrate that the bear maintains perfect protein balance during hibernation, although both protein synthesis and protein breakdown were lower than during summer. In contrast, during summer, bears are unable to reduce the net production of urea during starvation and, therefore, cannot preserve lean body mass.[12] This unique ability of bears to recycle urea during hibernation is not present in other hibernating mammals, such as the Columbian ground squirrel[26] or the hedgehog.[27]

The ability to prevent azotemia is a special and unparalleled feature of hibernating bears. One can also delay uremia in humans by administering diets low in protein and which are supplemented with essential amino acids.[28] However, as these diets block urea production rather than stimulate recycling, further studies of the mechanisms by which bears prevent the development of azotemia despite being anuric could provide new insights into the management of uremia. It would be of interest to test whether drugs that activate sirtuins may be of therapeutic value and reduce urea levels in humans.

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