Shop this Blog

Aquaporins in Skincare and Injectable Fillers

Écrit par : Dr. Leslie Baumann

|

|

Temps de lecture 16 min

As a dermatologist and skin care expert, patients often ask me about the latest skin care ingredients like aquaporins. Aquaporins have gained attention recently because their activity increases when SkinVive, a form of hyaluronic acid, is injected into the skin . But what are aquaporins and do they really hydrate your skin when added to creams? Here's what you need to know about aquaporins in skin care and the skin.

Aquaporin channel in Skin

What Are Aquaporins?

The definition of aquaporin is a pore that water and certain substances can pass through to move between cells. Aquaporins (AQPs) are integral membrane proteins that form water channels to facilitate water transport between cells. There are 13 types of aquaporins found in mammals. Aquaporins 1, 2, 4, 5 and 8 transport only water, while 3, 7, 9 and 10 also transport glycerol and other small solutes.

Skincare Products that Stimulate Aquaporin

Aquaporin itself does not work when you put it in skincare products, so do not look for aquaporin on the label. Instead look for ingredients that stimulate aquaporin activity.  Here are some products that act on aquaporin channels:

To find out which of these products is best for your skin type, take the skin type quiz and shop by your Baumann Skin Type (There are 16 skin types!)


skincare ingredients that act on aquaporin

How do Skincare Ingredients Activate AQP?

Though aquaporins themselves do not require energy, their activity can be stimulated by substances that increase their expression and accumulation in the cell membrane. For example, aquaporin expression and membrane localization is stimulated by growth factors and cytokines, increasing the number of aquaporin channels available for facilitated diffusion of water and solutes.

The key is that the aquaporin proteins themselves do not require energy to transport water/solutes, but their abundance and activity in the membrane can be upregulated by other cellular signaling processes that do require energy. The aquaporins then mediate passive, downhill water transport through the additional channels inserted in the membrane.

Skincare Ingredients That Act on Aquaporin

You will not see aquaporin listed on product labels, instead look for ingredients that stimulate aquaporin. The origianl wok on aquaporin was done by F. Bonte at Christian Dior skincare.  He showed that Ajuga turkentanica stimulated Aquaporin 3 and Dior was the first skincare line to have this technology.

Ajuga turkestanica

Ajuga turkestanica is an herb used in traditional medicine and bodybuilding supplements. It contains bioactive compounds like phytoecdysteroids and iridoid glycosides.

Studies show A. turkestanica extracts can increase aquaporin-3 (AQP3) expression and activity in skin cells. AQP3 is vital for shuttling water and glycerol between keratinocytes to hydrate skin.

In cultured human epidermal cells, A. turkestanica treatment elevated AQP3 protein levels. When applied topically on volunteers, it increased AQP3 gene expression and reduced transepidermal water loss.

Through stimulating AQP3, A. turkestanica improves epidermal differentiation and hydration. It enhances skin's natural moisturizing channels, leading to better barrier function.

A. turkestanica represents a unique botanical ingredient that acts on intrinsic aquaporin pathways. While aquaporins themselves don't penetrate skin, A. turkestanica provides a means of modulating these water transporters.

Cannabinoids

Recent studies 926) have uncovered a role for the cannabis-derived compound cannabidiol (CBD) in modulating aquaporins, specifically aquaporin-3 (AQP3). AQP3 is highly expressed in epidermal keratinocytes and is critical for skin hydration by transporting water and glycerol. In a study on hairless mice, daily topical application of 1% CBD solution significantly increased skin hydration. This moisturizing effect was accompanied by increased AQP3 expression in the skin at both the mRNA and protein levels. However, CBD did not alter other moisturizing factors like hyaluronic acid, ceramides or filaggrin. The selective stimulation of AQP3 indicates it likely contributes to CBD's skin hydrating properties.

CBD may increase AQP3 by activating PPARγ receptors, although the exact mechanisms are still unclear. Overall, CBD shows promise as a cosmetic ingredient capable of boosting skin hydration. By upregulating AQP3, CBD can enhance the skin's endogenous water retention and barrier function.

This face oil has cannabis seed oil, jojoba oil, moringa seed oil, rosa canina seed oil and linoleic acid to hydrate skin.  The cannabis will help stimulate aquaporin channels.

Glyceryl Glucoside

Glyceryl glucoside is a natural humectant that may stimulate aquaporin-3 (AQP3) activity to hydrate skin. AQP3 transports water and glycerol in epidermal keratinocytes, playing a key role in skin moisture balance.

In a study on cultured human keratinocytes, glyceryl glucoside increased AQP3 mRNA and protein levels. When applied topically on volunteers, glyceryl glucoside penetrated into intact epidermis and upregulated AQP3 gene expression.

This AQP3 stimulation was accompanied by improved barrier function, indicated by reduced transepidermal water loss. Glyceryl glucoside draws moisture into skin and stimulates skin's natural moisturizing channels.

 

Products with Glyceryl Glucoside:

This product is a superior barrier repair moisturizer.  It stimulates aquaporin channels, shows the maltese cross pattern under a microscope, and has the correct 1:1:1 ratio of ceramides, fatty acids and cholesterol.  It also contains many antiaging ingredients and ingredients to help protect the skin from pollution.

Retinoic acid

Retinoic acid, a derivative of vitamin A, has been widely used to treat skin conditions like abnormal keratinization, acne and skin aging. However, one of its most common side effects is dry, peeling skin and irritation. 


Some evidence suggests retinoids like retinol influence aquaporin expression.


A study (6) on cultured human HaCaT keratinocytes found retinoic acid drugs increased AQP3 mRNA, protein levels, and cell numbers. This aquaporin stimulation occurred with isotretinoin, acitretin, and adapalene treatment.


Higher aquaporin activity allows more water loss, potentially explaining retinoic acid’s drying effects. Proper dosing may reduce side effects while benefiting from AQP3’s barrier repair effects.

Overall, retinoic acid seems to modulate AQP3 expression in vitro. Further exploring this relationship and aquaporin regulation may improve retinoid therapy.


Below are some good retinols for beginners.  Retinol turns into retinoic acid in the skin.


Turmeric

The common spice turmeric contains the active compound curcumin. Studies show curcumin can increase AQP3 expression and glycerol transport in cultured human keratinocytes. It may act by activating PPARγ receptors. Applying turmeric extracts to mouse skin also elevates AQP3 levels. Turmeric's ability to boost aquaporins likely contributes to its skin hydrating benefits.


These skincare products have turmeric:

Dermal Fillers and AQP

Hyaluronic acid fillers like SkinVive, Restylane, Juvederm and Voluma have high water-binding capacity. When injected as dermal fillers, they absorb water from surrounding tissues. This causes the fillers to expand, which stretches and hydrates the skin. This mechanical action is believed to stimulate aquaporins, opening the water channels so they transport water more efficiently into skin cells. However, the exact mechanisms require further study for definitive confirmation.

Types of AQPs

Aquaporin 3

AQP3 is the main aquaporin in human epidermis and is permeable to both water and glycerol. For years scientists have known glycerol plays a key role in hydrating skin. The reasons became clearer after AQP3 was discovered. Studies show AQP3 defects in mice lead to epidermal dryness, decreased hydration, glycerol content, elasticity and impaired barrier recovery.

AQP5

Aquaporin-5 (AQP5) is another water channel protein found in the skin, specifically in sweat glands. AQP5 is highly expressed in the secretory coils and ducts of sweat glands. It plays a key role in producing and secreting sweat in response to heat or other stimuli. Studies in mice show AQP5 knockout impairs sweating, indicating its importance in sweat gland function. AQP5 may also help regulate epidermal proliferation and differentiation. Its expression was found reduced in some inflammatory skin diseases like atopic dermatitis, suggesting a potential involvement in disease pathogenesis. However, more research is still needed on the precise functions and regulations of AQP5 in skin physiology. Modulating AQP5 may present opportunities to treat certain sweat gland disorders like primary focal hyperhidrosis, which is characterized by excessive sweating. Overall, AQP5 represents another aquaporin integral to maintaining skin hydration and homeostasis through its sweat-producing role.

AQP9

This aquaporin 9 is only found in the stratum granulosum layer of the epidermis. It seems to transport glycerol and urea.

aquaporin hydration

How Do AQPs Hydrate Skin?

Aquaporins facilitate water, glycerol and solute transport between keratinocytes. This powers many skin functions like hydration, proliferation, differentiation and barrier repair.

AQP3 brings water and glycerol into cells. Glycerol acts as a natural moisturizing factor, while water maintains hydration. AQP3 also aids epidermal development and wound healing. Overall, aquaporins are dynamic channels that enable skin's constant hydration.

Getting AQP Into Skin

Topical products may contain aquaporins or "activate" them.  When formulated in skin care products, aquaporins are too large an these proteins  can't penetrate deep enough to have real impact when applied topically.

Instead, look for ingredients that boost natural aquaporin levels like ajuga turkenstancia, ceramides, niacinamide,  and turmeric. Retinoids and antioxidants help too by preventing UV-related declines in AQP3.

Injectables like Skinvivé (TM)  with hyaluronic acid are interesting because they seem to activate AQP3 in skin.

Aquaporins and the Skin Barrier

The skin moisture barrier prevents water loss and protects from irritants. When compromised like in dry skin or eczema, aquaporin activity changes:

  • AQP3 is increased, leading to excess water loss. 

  • AQP5 is reduced in inflammatory conditions, disrupting normal water balance. 

     

While not fully understood, aquaporins are vital for normal  barrier function.

aquaporins for inflammation

Aquaporins in Skin Inflammation

Rosacea

Recent studies have uncovered a role for aquaporin-3 (AQP3) in the inflammatory skin condition rosacea. Rosacea is characterized by facial redness, pimples, and dilated blood vessels.

One study (16) demonstrated that AQP3 is upregulated in the epidermal keratinocytes and dermal CD4+ T cells of rosacea patients and mouse models. In mice with rosacea induced by LL37 application, AQP3 knockout led to resistance to disease development.

In keratinocytes, AQP3 plays an essential role in NF-κB activation and subsequent chemokine production. NF-κB stimulates the release of chemokines that recruit immune cells, amplifying inflammation.

Additionally, AQP3 deficiency inhibited T helper 17 (Th17) cell differentiation, possibly by decreasing phosphorylated STAT3 levels. Th17 cells drive autoimmune responses and are implicated in rosacea.

Collectively, these findings suggest AQP3 is required for activating epidermal NF-κB and chemokine signaling. It also reveals a previously unknown role for AQP3 in Th17 cell-mediated immunity in rosacea pathogenesis.

 The  study shows AQP3 expression correlates with rosacea severity. This and other evidence suggests AQP3's involvement in the characteristic  inflammation of rosacea.

Indeed, AQP3 deletion attenuated the inflammatory phenotype in mice. Analyses revealed AQP3's participation in inflammation-related NF-κB and Th17 cell pathways. AQP3 may therefore be a novel therapeutic target for managing rosacea.

Acne

AQP3 expression and activity is increased in acne-affected skin compared to normal skin, facilitating greater water transport through the epidermis. This AQP3 upregulation may contribute to some pathophysiological features of acne including excess sebum production, abnormal keratinocyte proliferation and inflammation.

Research indicates that AQP3 is overexpressed in acne lesions versus non-lesional skin. By increasing water permeability in the epidermis, altered AQP3 expression and function may be implicated in acne pathogenesis. However, more research is still needed to fully understand its specific contributions.

Aquaporins enable hydration, barrier function and more by shuttling water and solutes between cells. While topical aquaporins likely don't work, modulating them with ingredients, medications or specialized injectables has promise.


To find the best skincare products for your skin type, take the skin care routine quiz and build a custom skin care routine from many brands.


[[ctaquiz]]

Level up your skin care knowledge with medical advice from dermatologists

How do aquaporins work?

AQPs are protein channels embedded in the cell membranes of skin that allow water to pass through while preventing the passage of ions and other solutes. By allowing water to permeate through skin cells, aquaporins play an important role in regulating hydration, temperature control, and other functions related to water balance in skin.

Why are aquaporins important?

AQPs are important in skin because they allow water, glycerol, and urea to pass through the plasma membranes between skin cells, enabling water transport that is crucial for hydration, temperature regulation, and other functions. Since the plasma membranes are otherwise impermeable to water, aquaporins provide the only pathway for water to cross between skin cells.

Are aquaporins active transport?

AQPs facilitate passive transport of water and small solutes across cell membranes down their concentration gradients, rather than active transport against a concentration gradient.

Do Aquaporins Use ATP?

No, AQPs do not use ATP. Aquaporins facilitate passive diffusion of water and small solutes across cell membranes, rather than active transport, so they do not require or use ATP as an energy source.

Who discovered aquaporins in skin?

The complete timeline for the discovery of aquaporin 3 (AQP3) expression in human skin, with references is: In 1993, AQP3 was first identified and cloned from rat kidney by two independent groups: Agre et al. "New aquaporin AQP3: cDNA and functional expression in Xenopus laevis oocytes." Proceedings of the National Academy of Sciences 90.3 (1993): 814-818. Ishibashi et al. "Molecular cloning and expression of a member of the aquaporin family with permeability to glycerol and urea in addition to water expressed at the basolateral membrane of kidney collecting duct cells." Journal of Biological Chemistry 269.14 (1994): 10697-10702. In 2002, Sougrat et al. published the first study demonstrating AQP3 expression in human skin epidermis and reconstructed epidermis: Sougrat et al. "Functional expression of AQP3 in human skin epidermis and reconstructed epidermis." Journal of Investigative Dermatology 118.4 (2002): 678-685. In 2006, Olsson et al. also published on the characterization of AQP3 in human skin: Olsson et al. "Identification of AQP5 in Human Skin and Verification of its Expression in Human Sweat Glands." Journal of Biological Chemistry 281.27 (2006): 18997-19007. So in summary, Sougrat et al. in 2002 were the first to publish experimental evidence of AQP3 localization in human skin,. The initial identification of AQP3 was in rat kidney in 1993 by Agre and Ishibashi groups.

What is an aquaporin?

AQPs are integral membrane proteins that form pores in the membrane of biological cells to facilitate transport of water and small solutes. By providing a channel for the passive movement of water molecules in and out of a cell, aquaporins play an essential role in maintaining water homeostasis in many tissues and organ systems.

Are aquaporins found in all cells?

AQPs are expressed in many cell types, but not ubiquitously in all cells; for example, they are present in keratinocytes in the skin and epithelial cells in the kidney, but not typically found in fibroblasts and other connective tissue cells. The specific types of aquaporins expressed depends on the physiological water transport functions required by that tissue or organ.

Why do water molecules need aquaporin?

Cell membranes are impermeable to water without aquaporins because of the hydrophobic bilayer structure of cell membranes.. AQPs form selective pore channels that allow rapid passive diffusion of water across the cell membrane, down its concentration gradient, enabling water transport that is essential for many physiological processes.

Where are aquaporins located?

In the skin, aquaporins are located within the plasma membranes of keratinocytes in the epidermal layers, particularly abundant in the basal and spinous layers.

Do aquaporins require energy?

Aquaporins facilitate the passive transport of water and small solutes across cell membranes down their concentration gradients, so they do not require ATP or other energy sources.

How do aquaporins work?

Aquaporins are protein channels that allow water and small solutes to pass through the membrane of cells while preventing the passage of ions and other solutes. When water molecules come into contact with an aquaporin pore, they are reoriented and passed through the pore in single file by transient interactions with the amino acids lining the aquaporin channel. The key points are that 1) aquaporins provide a selective channel that allows only water and small solutes to cross the cell membrane and 2) they transport water in single file through specific interactions and orientations as water passes through the pore. This facilitates rapid passive movement of water down its concentration gradient.

Where are aquaporins found?

AQPs are found in the cell membranes of many cell types throughout the body, but are highly expressed in tissues involved in fluid transport. Some key locations are: Kidney - Aquaporins are critical for water reabsorption in the renal tubules. Skin - Keratinocytes in the epidermis contain aquaporins for hydration. Lungs - Aquaporins in the alveolar epithelial cells are involved in air humidity regulation. Secretory glands - Aquaporins allow water secretion in salivary glands, sweat glands, etc. Eyes - Aquaporins facilitate water circulation in the cornea, lens and other ocular tissues. Brain - Astrocytes, ependymal cells and other brain cells express aquaporins to regulate cerebrospinal fluid. Blood vessels - Aquaporins control water exchange between blood and interstitial fluid. So in summary, aquaporins are found throughout the body but are most abundant in cells involved in water transport functions.

Can water pass thorough cell membranes?

Water must pass through aquaporin channels to move cell to cell. There are many types of AQP channels.

Do aquaporins require a living cell to function?

Aquaporins can facilitate water transport through membranes even in artificial vesicles or after isolation from cells, indicating they passively transport water down its concentration gradient and do not require cellular energy or metabolism. This allows the effects of skin care ingredients on aquaporin function to be studied in the lab on ex vivo skin samples and artificial skin models. The key advantage is that since aquaporins don't require living cells to transport water, their activity can be examined by inserting them into artificial membranes and skin constructs in vitro. This allows for controlled experiments on how different compounds influence water movement through aquaporins in skin models that mimic human skin.

Best References and Scientific Publications on Aquaporin

  1. Baumann L. Moisturizers in Ch. 43 of Baumann's Cosmetic Dermatology Ed 3. (McGraw Hill 2022)
  2. Baumann, L. Chapters 29 and 30.  Cosmeceuticals and Cosmetic Ingredients (McGraw Hill 2015)
  3. Boury-Jamot, M., Daraspe, J., Bonté, F., Perrier, E., Schnebert, S., Dumas, M., & Verbavatz, J. M. (2009). Skin aquaporins: function in hydration, wound healing, and skin epidermis homeostasis. Aquaporins, 205-217.
  4. Dumas, M., Sadick, N. S., Noblesse, E., Juan, M., Lachmann-Weber, N., Boury-Jamot, M., ... & Bonté, F. (2007). Hydrating skin by stimulating biosynthesis of aquaporins. Journal of drugs in dermatology: JDD, 6(6 Suppl), s20-4.
  5. Sougrat, R., Morand, M., Gondran, C., Bonté, F., Dumas, M., & Verbavatz, J. M. (2000). Functional expression of AQP3 in human epidermis and keratinocyte cell cultures. In Molecular biology and physiology of water and solute transport (pp. 179-183). Boston, MA: Springer US.
  6. Xing, F., Liao, W., Jiang, P., Xu, W., & Jin, X. (2016). Effect of retinoic acid on aquaporin 3 expression in keratinocytes. Genet Mol Res, 15(15016951), 9.
  7. Bonté, F., Noblesse, E., Juan, M., Verbawatz, J. M., & Dumas, M. (2009). A study on the importance of aquaporins for human skin. Chinese Journal of Dermatology, 42(5), 327-329.
  8. Xing, F., Liao, W., Jiang, P., Xu, W., & Jin, X. (2016). Effect of retinoic acid on aquaporin 3 expression in keratinocytes. Genet Mol Res, 15(15016951), 9.
  9. Boury-Jamot, M., Sougrat, R., Tailhardat, M., Le Varlet, B., Bonté, F., Dumas, M., & Verbavatz, J. M. (2006). Expression and function of aquaporins in human skin: Is aquaporin-3 just a glycerol transporter?. Biochimica et Biophysica Acta (BBA)-Biomembranes, 1758(8), 1034-1042.
  10. Takata K, Matsuzaki T, Tajika Y. Aquaporins: water channel proteins of the cell membrane. Prog Histochem Cytochem. 39:1, 2004
  11. Choi EH, Man MQ, Wang F, et al. Is endogenous glycerol a determinant of stratum corneum hydration in humans? J Invest Dermatol. 125:288, 2005
  12. Hara M, Ma T, Verkman AS. Selectively reduced glycerol in skin of aquaporin-3-deficient mice may account for impaired ski hydration, elasticity, and barrier recovery. J Biol Chem. 277:46616, 2002.
  13. Hara M, Verkman AS. Glycerol replacement corrects defective skin hydration, elasticity, and barrier function in aquaporin-3-deficient mice. Proc Natl Acad Sci U S A. 100:7360, 2003.
  14. Cao C, Wan S, Jiang Q, et al. All-trans retinoic acid attenuates ultraviolet radiation-induced down-regulation of aquaporin-3 and water permeability in human keratinocytes J Cell Physiol. 215:506, 2008.
  15. Sugiyama, Y., Yamazaki, K., Kusaka-Kikushima, A., Nakahigashi, K., Hagiwara, H., & Miyachi, Y. (2014). Analysis of aquaporin 9 expression in human epidermis and cultured keratinocytes. FEBS Open Bio, 4, 611-616.
  16. Tricarico, P. M., Mentino, D., De Marco, A., Del Vecchio, C., Garra, S., Cazzato, G., ... & Calamita, G. (2022). Aquaporins are one of the critical factors in the disruption of the skin barrier in inflammatory skin diseases. International Journal of Molecular Sciences, 23(7), 4020.
  17. Dumas M, Gondran C, Barré P, et al. Effect of an Ajuga turkestanica extract on aquaporin 3 expression, water flux, differentiation and barrier parameters of the human epidermis. Eur J Dermatol.12:XXV, 2002.
  18. SKINVIVE™ by JUVÉDERM® Patient Label 2023.
  19. Safa M., Natalizio A., Hee, CK. A Prospective, Open-Label Study to Evaluate the Impact of VYC-12L Injection on Skin Quality Attributes in Healthy Volunteers. Clinical, Cosmetic and Investigational Dermatology. 2022.
  20. SKINVIVE™ by JUVÉDERM® Directions for Use 2023.
  21. Nakab L., Hee CK, Guetta O. Improvements in Skin Quality Biological Markers in Skin Explants Using Hyaluronic Acid Filler VYC-12L. Plastic Reconstr Surg Glob Open.
  22. Yin, Z., & Ren, H. (2023). Aquaporins in Skin. In Aquaporins (pp. 211-223). Singapore: Springer Nature
  23. Chen, M., Peng, Q., Tan, Z., Xu, S., Wang, Y., Wu, A., ... & Deng, Z. (2023). Targeting Aquaporin-3 Attenuates Skin Inflammation in Rosacea. International Journal of Biological Sciences, 19(16), 5160-5173. Singapore. 2020.
  24. Ramos Del Cano, L. (2023). Dissecting the Role of Aquaporin 5 in Epidermal Barrier Function.
  25. Camilion, J. V., Khanna, S., Anasseri, S., Laney, C., & Mayrovitz, H. N. (2022). Physiological, pathological, and circadian factors impacting skin hydration. Cureus, 14(8).
  26. Ikarashi, N., Shiseki, M., Yoshida, R., Tabata, K., Kimura, R., Watanabe, T., ... & Kamei, J. (2021). Cannabidiol application increases cutaneous aquaporin-3 and exerts a skin moisturizing effect. Pharmaceuticals, 14(9), 879.
  27. Shahid, H., Shahzad, M., Shabbir, A., & Saghir, G. (2019). Immunomodulatory and anti-inflammatory potential of curcumin for the treatment of allergic asthma: effects on expression levels of pro-inflammatory cytokines and aquaporins. Inflammation, 42, 2037-2047.

Aquaporin image attribution: OpenStax College - Anatomy & Physiology, Connexions Web site.http://cnx.org/content/col11496/1.6/, Jun 19 2013.,Commons.wikimedia.org/w/index.php?curid=30148553