Aquaglyceroporins: Drug Targets for Metabolic Diseases?

Calamita, Giuseppe; Perret, Jason; Delporte, Christine

doi:10.3389/fphys.2018.00851

Cited by 55 publications

(46 citation statements)

References 164 publications

(288 reference statements)

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“…Obesity is regularly associated with hormonal dysregulation [ 41 , 42 ]. In addition, obesity is related with alterations in the expression and function of the aquaglyceroporins and consequently in glycerol transport [ 43 , 44 ]. Obese men are known to have a positive correlation with abnormal sperm morphology, decreased sperm concentration and sperm motility, decreased serum testosterone and increased E2 levels compared with healthy men, which consequently leads to compromised fertility [ 45 , 46 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

Estrogen Modulates Glycerol Permeability in Sertoli Cells through Downregulation of Aquaporin-9

Bernardino

Carrageta

Silva

et al. 2018

Cells

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High 17β-Estradiol (E2) levels are known to cause alterations of spermatogenesis and environments throughout the male reproductive tract. Sertoli cells (SCs) ensure an adequate environment inside the seminiferous tubule. Glycerol stands as essential for the maintenance of blood–testis barrier created by SCs, however, the role of E2 in this process is not known. Herein, we hypothesized that the effect of E2 on glycerol permeability in mouse SCs (mSCs) could be mediated by aquaglyceroporins. The expression of aquaglyceroporins was assessed by RT-PCR and qRT-PCR. Glycerol permeability was evaluated by stopped-flow light scattering. We were able to identify the expression of AQP3 and AQP9 in mSCs where AQP9 is more abundant than AQP3. Our results show that high E2 levels decrease AQP9 mRNA abundance with no influence on AQP3 in mSCs. Interestingly, high E2 levels decreased mSCs’ permeability to glycerol, while downregulating AQP9 expression, thus suggesting a novel mechanism by which E2 modulates fluid secretion in the testis. In conclusion, E2 is an important regulator of mSCs physiology and secretion through changes in AQP9 expression and function. Thus, alterations in glycerol permeability induced by E2 may be the cause for male infertility in cases associated with the presence of high E2 levels.

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Section: Discussionmentioning

confidence: 99%

Estrogen Modulates Glycerol Permeability in Sertoli Cells through Downregulation of Aquaporin-9

Bernardino

Carrageta

Silva

et al. 2018

Cells

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“…AQPs 11 and 12 are more distantly related to other mammalian AQPs, based on amino acid sequence; functions and regulation remain to be fully defined [ 19 ]. Diverse contributions of AQP classes could augment pro-cancer conditions by enhancing signaling via nitric oxides or hydrogen peroxide [ 20 , 21 , 22 , 23 ], facilitating gas exchange of O 2 and CO 2 [ 24 , 25 ], promoting cell cycle progression [ 26 ], providing metabolic support [ 27 , 28 ], mediating dual ion and water fluxes for localized control of process extension [ 12 ], driving angiogenesis [ 29 ], boosting mechanical compliance needed for rapid volume changes [ 6 , 30 ] and other processes. Dynamic translocation between membrane and intracellular vesicle pools is controlled by signaling; for example, AQP2 localization depends on cyclic AMP-dependent kinase activity [ 31 ], and AQPs are associated via protein–protein interactions into signaling complexes [ 32 , 33 , 34 ].…”

Section: Introductionmentioning

confidence: 99%

Combined Systematic Review and Transcriptomic Analyses of Mammalian Aquaporin Classes 1 to 10 as Biomarkers and Prognostic Indicators in Diverse Cancers

Chow

Bowen

Yool

2020

Cancers

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Aquaporin (AQP) channels enable regulated transport of water and solutes essential for fluid homeostasis, but they are gaining attention as targets for anticancer therapies. Patterns of AQP expression and survival rates for patients were evaluated by systematic review (PubMed and Embase) and transcriptomic analyses of RNAseq data (Human Protein Atlas database). Meta-analyses confirmed predominantly negative associations between AQP protein and RNA expression levels and patient survival times, most notably for AQP1 in lung, breast and prostate cancers; AQP3 in esophageal, liver and breast cancers; and AQP9 in liver cancer. Patterns of AQP expression were clustered for groups of cancers and associated with risk of death. A quantitative transcriptomic analysis of AQP1-10 in human cancer biopsies similarly showed that increased transcript levels of AQPs 1, 3, 5 and 9 were most frequently associated with poor survival. Unexpectedly, increased AQP7 and AQP8 levels were associated with better survival times in glioma, ovarian and endometrial cancers, and increased AQP11 with better survival in colorectal and breast cancers. Although molecular mechanisms of aquaporins in pathology or protection remain to be fully defined, results here support the hypothesis that overexpression of selected classes of AQPs differentially augments cancer progression. Beyond fluid homeostasis, potential roles for AQPs in cancers (suggested from an expanding appreciation of their functions in normal tissues) include cell motility, membrane process extension, transport of signaling molecules, control of proliferation and apoptosis, increased mechanical compliance, and gas exchange. AQP expression also has been linked to differences in sensitivity to chemotherapy treatments, suggesting possible roles as biomarkers for personalized treatments. Development of AQP pharmacological modulators, administered in cancer-specific combinations, might inspire new interventions for controlling malignant carcinomas.

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“…MR309, a Sigma-1 antagonist is currently in Phase II clinical trial for the treatment of neuropathic pain) [31,49,50]. On the other hand, aquaporins are still largely unexplored from a medicinal chemistry standpoint and have been recognized as druggable molecular targets only recently [17,[51][52][53][54][55]. To the best of our knowledge, this represents the first report involving modulators of both AQP and S1R.…”

Section: Discussionmentioning

confidence: 90%

Dual Aquaporin and Sigma1 Receptor (DAS) Modulators: New Tools for Counteracting Oxidative Stress

Pellavio¹,

Rossino²,

Gastaldi³

et al. 2020

Preprint

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Specific aquaporins (AQP), called peroxyporins, play a relevant role in controlling H2O2 permeability and ensure reactive oxygen species wasting during oxidative stress. Another target involved in oxidative stress is the Sigma1 Receptor (S1R), since its activation is triggered by oxidative or endoplasmic reticulum stress. Herein we evaluated the effect of S1R modulators on AQP-dependent water permeability in the presence and in the absence of oxidative stress. Applying stopped-flow light scattering and fluorescent probe methods, water and hydrogen peroxide permeability in Hela cells have been studied. Results evidenced that S1R agonists can restore water permeability in heat-stressed cells and the co-administration with a S1R antagonist totally counteracted the ability to restore the water permeability. All compounds except one were able to counteract the oxidative stress of HeLa cells specifically knocked down for S1R. Taken together, our results support the hypothesis that the investigated compounds act as dual aquaporin and Sigma1 receptor (DAS) modulators. The finding that small molecules can modulate both AQP and S1R opens a new direction toward the identification of innovative drugs able to regulate cell survival during oxidative stress in pathologic conditions, like cancer and degenerative diseases.

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Aquaglyceroporins: Drug Targets for Metabolic Diseases?

Cited by 55 publications

References 164 publications

Estrogen Modulates Glycerol Permeability in Sertoli Cells through Downregulation of Aquaporin-9

Estrogen Modulates Glycerol Permeability in Sertoli Cells through Downregulation of Aquaporin-9

Combined Systematic Review and Transcriptomic Analyses of Mammalian Aquaporin Classes 1 to 10 as Biomarkers and Prognostic Indicators in Diverse Cancers

Dual Aquaporin and Sigma1 Receptor (DAS) Modulators: New Tools for Counteracting Oxidative Stress

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