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Department of Biology, University of Ottawa, Ottawa, Ontario, Canada K1N 6N5
Address all correspondence and requests for reprints to: K. M. Gilmour, Department of Biology, University of Ottawa, 150 Louis Pasteur, Ottawa, Ontario, Canada K1N 6N5. E-mail: katie.gilmour{at}science.uottawa.ca.
In tetrapod vertebrates, aldosterone is the main mineralocorticoid hormone, playing a key role in the regulation of sodium transport across epithelia. Metabolic functions are regulated by the glucocorticoid hormones cortisol and/or corticosterone. The mineralocorticoid and glucocorticoid hormones are produced by the adrenal cortex and exert their effects through separate, well-characterized receptors belonging to the superfamily of steroid hormone receptors that act as ligand-dependent transcription factors (1). By contrast, most fish appear to lack aldosterone; neither attempts to measure the hormone itself (2) nor attempts to find an enzyme with significant aldosterone synthesizing activity have been successful (3, 4). Cortisol is the principal corticosteroid produced by the interrenal tissue, the piscine equivalent of the adrenal cortex, and contributes to the regulation of salt and water balance as well as metabolism (5). Yet despite the apparent absence of a selective mineralocorticoid hormone, fish possess, as Sturm et al. report in this issue of Endocrinology (6), mineralocorticoid receptors (MRs). Their work reopens the debate about whether fish possess a mineralocorticoid hormone, while at the same time adding to a recent but growing body of evidence supporting the presence of multiple corticosteroid receptors in teleost fish (7, 8, 9).
Sturm et al. (6) cloned two MR isoforms from rainbow trout and examined their activation by various corticosteroids. As expected, cortisol was a potent agonist of the trout MRs, exhibiting EC50 values of 0.5–1.1 nM. This sensitivity to cortisol is similar to or greater than that of the trout glucocorticoid receptors (GRs), which exhibit EC50 values of 0.7–46 nM (9). A similar comparison has been made for only one other fish species, a cichlid, and here again the MR appears to be more sensitive to cortisol than the GRs (7). In this regard, the fish MRs parallel their mammalian counterparts, which are considered to be high-affinity cortisol receptors. Indeed, the high affinity of the mammalian MR for cortisol coupled with the approximately 100-fold higher circulating levels of glucocorticoids than aldosterone would result in continuous activation of MRs by cortisol were it not for the presence of a cellular sentinel that excludes cortisol from some MR-expressing cells. In the mammalian kidney, for example, MRs are coexpressed with the enzyme 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD) which inactivates cortisol but not aldosterone, conferring selective activation by the mineralocorticoid hormone (10). Whether a similar protective mechanism exists in fish remains to be determined, but fish do at least possess the necessary enzyme (11) and a variety of tissues exhibit both MR and 11ß-HSD gene expression (6, 7, 11).
If selective mineralocorticoid activation of the fish MR is in fact possible, what is the compound with selective mineralocorticoid action in fish? Sturm et al. (6) surveyed a number of corticosteroids and found that, in addition to aldosterone, 11-deoxycorticosterone was the most potent activator of the trout MRs; EC50 values for aldosterone and 11-deoxycorticosterone were about 10 times lower than those for cortisol. Like aldosterone, 11-deoxycorticosterone is a selective MR agonist: it does not activate the trout GR (9). Unlike the situation for aldosterone, however, the capacity to synthesize 11-deoxycorticosterone is present in fish (Fig. 1
; Ref. 12) and, although data are sparse, the compound itself appears to be present in fish blood at levels that are not only measurable but are comparable to the concentrations required to activate the trout MR (13). In suggesting the potential for 11-deoxycorticosterone to function as a fish mineralocorticoid hormone, Sturm et al. (6) have presented an intriguing challenge to the research community. To establish 11-deoxycorticosterone as a physiologically significant fish MR ligand in vivo will require that changes in circulating 11-deoxycorticosterone levels occur in response to a relevant disturbance, and that physiological responses appropriate for the correction of that disturbance be initiated by 11-deoxycorticosterone administration. However, the physiological consequences of MR activation in fish have yet to be identified.
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Studies of such euryhaline species have revealed a key regulatory role for cortisol (5, 17). Cortisol levels increase when euryhaline fish are transferred from fresh water to sea water, and cortisol treatment improves salinity tolerance, in part by increasing the activity of a key element of the gill salt-secreting mechanism, Na+-K+-ATPase. However, parallel increases in salt uptake and the prevalence of ion transporting cells in the gills occur after cortisol treatment in freshwater fish. Additionally, transient increases in cortisol levels accompany transfer to more dilute environments. Thus, cortisol appears to be a piscine switch hitter, promoting salt secretion in sea water but salt uptake in fresh water (17). Interestingly, at least some of these mineralocorticoid actions of cortisol are mediated by GRs. Gill GR gene expression (18, 19) and numbers increase with seawater acclimation (20), and these changes translate into greater stimulation of Na+-K+-ATPase activity by cortisol (17). Also, the intestinal absorption of imbibed water that accompanies the transition from fresh water to sea water in developing salmon was inhibited by GR blockade (21). To what extent MRs are regulated by salinity changes remains to be determined, as do the osmoregulatory responses that are linked to MR activation. Indeed, unraveling the roles of GRs and MRs in the maintenance of salt and water balance in fish will require patience and ingenuity, given the suite of corticosteroid receptors that has been identified in two teleost fish (6, 7, 8, 9). This process must also take into consideration possible mechanisms, such as 11ß-HSD, that may regulate access to the two receptor types. Finally, in light of the findings of Sturm et al. (6), a clear need exists to measure 11-deoxycorticosterone levels during osmoregulatory disturbances and to readdress the question of whether fish possess a selective mineralocorticoid hormone.
Fish MRs are broadly distributed beyond the tissues (such as gill; Fig. 2) that are important in salt and water balance. Interestingly, of the 12 rainbow trout tissues examined by Sturm et al. (6), MR mRNA levels were highest in brain. Brain was also the only cichlid tissue examined that displayed greater MR than GR gene expression (7). In mammals, MRs are found in the brain in the absence of 11ß-HSD expression. Without the protective effect of 11ß-HSD, brain MRs probably function as high-affinity cortisol receptors, but identifying the physiological roles of brain MRs vs. GRs is an ongoing challenge (22). Thus, investigating the physiological functions of fish MRs in nontraditional tissues is yet another item to add to the growing "to-do" list. In short order, corticosteroid signaling in fish has expanded from a one hormone-one receptor system to a system encompassing multiple receptor types (6, 7, 8, 9) and, given the findings of Sturm et al. (6), potentially multiple hormones. Additional fishing for answers will clearly be required to fully elucidate the complexity of this corticosteroid signaling system.
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Received October 21, 2004.
Accepted for publication October 26, 2004.
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