Aquaporins (AQPs) belong to the membrane intrinsic protein (MIP) family [
140] and are found in practically all living organisms [
141]. AQPs are tetrameric, small (25–34 kDa), hydrophobic proteins that constitute integral membrane channels [
142]. The main function of AQPs is water transport and flux water regulation in cellular membranes [
143]. Since their discovery, AQPs have been the focus of many studies, given the importance of water transport in all biological processes, and have been shown to be involved in several diseases of different tissues [
144]. Specifically, nine of the thirteen total AQPs (AQP1, 2, 3, 4, 5, 6, 8, 9, and 11) discovered in mammals have been identified as existing in the human female reproductive tract [
145]. Proper water transport and homeostasis is crucial for normal reproductive performance and, thus, these AQPs play key roles in the female reproductive system, as they are involved in vaginal lubrication, cervical ripening, implantation, uterine water inhibition, blastocyst formation, ovum transport, follicle maturation, and oocyte cryopreservation [
145]. However, apart from the main described functions, some aquaporins are also involved in biological alterations of the reproductive system such as cell migration, proliferation, carcinogenesis, and inflammatory processes [
146,
147]. As previously described, these processes are crucial for the development of endometriosis, and thus, the link between AQPs and the pathogenesis of endometriosis must be further explored [
148]. AQP1 might have a role in endometriosis via the Wnt/β-catenin signaling pathway. Hence, AQP1 gene silencing entails a decrease in the adhesion and invasion of ectopic endometrial cells, as well as a decrease in angiogenesis and an increase in the apoptosis rate of these cells [
149]. In the same way, AQP5, whose expression is menstrual cycle-dependent [
150], is more highly expressed in eutopic as compared with ectopic endometrial cells in women with endometriosis [
151]. Another investigation reported that AQP5 expression was induced by estrogen through activation of the estrogen-response element (ERE) in the promoter region of the AQP5 gene [
152]. Therefore, it could be related to endometrial cell invasion and proliferation. This aspect was observed in a study where overexpression of AQP5 promoted endometrial tumor cell migration, while knockdown of AQP5 decreased migration of these cells [
153]. Moreover, Choi et al. [
154] described that AQP2 and AQP8 expression was significantly increased in the eutopic endometrial cells of patients with endometriosis as compared with a control group. Also, this work stated that the endometrial expression of AQP9 was significantly decreased in the eutopic endometrium of patients with endometriosis as compared with that of healthy women. Besides, it was demonstrated that the down-regulation of AQP9 increased cell migration and invasion through the activation of the ERK/p38 MAPK signaling pathways. These results are consistent with the demonstration of changes in the expression of AQP9 in several types of cancer and inflammatory diseases [
155], which suggests that AQP9 could also play an important role in the pathogenesis of endometriosis.
Additionally, it has been reported that the expression of AQP1, present in macrophages, regulated their migration in a murine model of peritonitis [
156], showing that functional AQP1 suppresses the migration of resting macrophages. Further, the expression of AQP1 was found to attenuate macrophage-mediated inflammatory responses in LPS-induced acute kidney injury by inhibiting ERK and p38 MAPK activation [
157]. In addition, AQP3 has shown to be a key component in the immune function of macrophages through its participation in water and glycerol membrane transportation, as well as in their phagocytic and migration activity [
147]. Furthermore, AQP4 blockade alleviated the development and severity of irradiated lung damage in a mouse model. This was associated with attenuated infiltration of inflammatory cells, decreased production of pro-inflammatory cytokines, and inhibited activation of M2 macrophages [
158].
Therefore, the available results suggest that a relation between AQPs and endometriosis would not only be mediated by their role as water membrane channels (
Figure 2), which is their major physiological function [
143]. Their involvement in several intracellular signaling pathways as signal regulating factors (via transporting molecules or coupling with other proteins) [
159] should be taken into account. Particularly, AQPs 1, 2, 8, and 9 could be related to endometriosis due to their participation in different signaling pathways such as Wnt/β-catenin, ERK/p38 MAPKm, and PI3K/Akt [
149,
152,
154]. Hence, more studies are needed to reveal the actual signaling regulatory function of AQPs. In contrast, the roles of AQP1 and 5 in different inflammatory processes, whose regulation is altered in endometriosis (displaying maintained or increased expression), could be mediated by their roles in water fluid homeostasis as water transporters, and thus their potential relevance in endometriosis should be also further investigated [
147,
160].
Modulation of Aquaporins by Bioactive Compounds: Further Targeted Therapies
The modulation of the presence or functionality of aquaporins by bioactive compounds or drugs may provide new opportunities for therapeutic applications in a variety of diseases that involve alterations of cellular homeostasis and inflammatory processes [
161]. In this sense, gating of the AQP channel by different non-covalent small molecule inhibitors has been reported [
162]. Blockers of AQP4 have demonstrated a positive effect in ischemia-mediated cerebral edema models [
163]. Also, some of the quaternary ammonium compounds [
164,
165,
166], arylsulfonamide-based carbonic anhydrase inhibitors [
167,
168], and certain anti-epileptics [
169] have been suggested to be selective blockers of AQP1 and AQP4. Furthermore, on the other hand, there are pharmacological synergists to AQP functionality, i.e., the aryl sulfonamide-related derivatives [
170] and the chemical derivative of the arylsulfonamide compound furosemide [
166], that directly and specifically potentiate AQP-mediated water transport.
Aberrant expression of AQPs in eutopic and ectopic endometrial cells could be a target of action against endometriosis disease. Some studies of endometriosis cell models have reported a deficit in antioxidant enzymes and, thus, a low antioxidant capacity. Therefore, excess accumulation of reactive oxygen species could play a role in the infertility associated with endometriosis [
171]. AQP8 has been reported as a fine regulator of redox signal transduction since it regulates permeability to water and H
2O
2 under stress conditions [
172]. As described above, AQP8 is overexpressed in eutopic endometrial cells of women with endometriosis [
154]. Hence, the regulation of AQP8 expression could reduce the level of ROS in cells, therefore reducing oxidative stress. This could favor better evolution of endometriosis. In this sense, a recent study carried out in the erythromegakaryocytic cell line B1647 showed a downregulation of AQP8 expression with low doses of SFN (10–30 µM) [
173]. Therefore, SFN could be a good therapy to regulate AQP8 expression in endometrial cells and decrease oxidative stress in these cells.
Furthermore, if we consider that endometriosis is an estrogen-dependent disease [
174], new therapies that counter the effect of estradiol need to be explored. Estrogens are steroid hormones that regulate AQP expression in the female reproductive system [
175]. The expression of AQP2 and AQP5, which is up-regulated in endometrial cells and seem to play a role in the estrogen-related migration, invasion, adhesion, and proliferation of these cells, could be regulated to act on the ERE located in the promoters of the genes encoding AQP2 and AQP5 [
152,
176]. In some studies, SFN [
177] and I3C [
178,
179,
180] have been shown to be modulators of the estrogen effects in several types of cancer. Given the common features of cancer and endometriosis, these compounds could induce changes in the ERE of the AQP5 gene, thus regulating its expression. In the same way, it has been reported that sulforaphane protects the central nervous system in traumatic brain injury patients by reducing the loss of AQP4 in the injury core and increasing the level of AQP4 in the penumbra region [
181,
182].
All of the above data indicate that AQP activity can be modified through distinct mechanisms. However, it is also important to consider that pharmacological and bioactive natural compounds might interact regarding AQP expression and/or functionality, reflecting diverse affinity and efficacy. Therefore, it has become clear that the investigation of plant biomolecules as glucosinolates/isotiocyanates that target the modulation of AQPs is an interesting research objective, especially as these are natural compounds with fewer side effects than other therapeutic agents.