Aquaporins in clinical medicine

Abstract

The aquaporins are a family of membrane water channels, some of which also transport glycerol. They are involved in a wide range of physiological functions (including water/salt homeostasis, exocrine fluid secretion, and epidermal hydration) and human diseases (including glaucoma, cancer, epilepsy, and obesity). At the cellular level, aquaporin-mediated osmotic water transport across cell plasma membranes facilitates transepithelial fluid transport, cell migration, and neuroexcitation; aquaporin-mediated glycerol transport regulates cell proliferation, adipocyte metabolism, and epidermal water retention. Genetic diseases caused by loss-of-function mutations in aquaporins include nephrogenic diabetes insipidus and congenital cataracts. The neuroinflammatory demyelinating disease neuromyelitis optica is marked by pathogenic autoantibodies against astrocyte water channel aquaporin-4. There remain broad opportunities for the development of aquaporin-based diagnostics and therapeutics. Disease-relevant aquaporin polymorphisms are beginning to be explored. There is great promise in the development of small-molecule aquaporin modulators for therapy of some types of refractory edema, brain swelling, neuroinflammation, glaucoma, epilepsy, cancer, pain, and obesity.

Figure 1

Roles of water-selective aquaporins (AQPs, shown in purple). (a) Kidney nephron. High transepithelial water permeability in proximal tubule, thin descending limb of Henle (TDLH), vasa recta, and collecting duct is required for urinary concentrating function. (b) Epithelial fluid secretion (exocrine glands, ICP/IOP, etc.). High transepithelial water permeability facilitates active, near-isosmolar fluid secretion. (c) Brain water balance (cytotoxic and vasogenic edema). High water permeability across blood–brain and blood–CSF barriers facilitates water movement into and out of brain. (d) Cell migration (angiogenesis, tumor metastasis, glial scarring, etc.). AQP-facilitated cell migration involves water entry into protruding lamellipodia in migrating cells. (e) Neuroexcitation (neurosensory function, seizure activity, etc.). AQP4-facilitated water transport in astrocytes during K⁺ reuptake following neuroexcitation causes extracellular space contraction, maintaining the driving force for K⁺ reuptake. Abbreviations: CSF, cerebrospinal fluid; ICP, intracranial pressure; IOP, intraocular pressure.

Figure 2

Roles of water/glycerol-transporting aquaporins (aquaglyceroporins). (a) Cell proliferation (tumor growth, wound healing, etc.). AQP3 maintains high cellular glycerol for generation of ATP and biosynthesis. (b) Skin hydration. AQP3 maintains high stratum corneum glycerol, which acts as a humectant to retain water. (c) Adipocyte metabolism. AQP7 facilitates glycerol exit from adipocytes, preventing intracellular glycerol and triglyceride accumulation. Abbreviations: AQP, aquaporin; ATP, adenosine triphosphate; FFA, free fatty acid(s); TG, triglyceride(s).