Aquaporins in lung health and disease: Emerging roles, regulation, and clinical implications

Abstract

Aquaporins (AQPs) aka water channels are a family of conserved transmembrane proteins (~30 kDa monomers) expressed in various organ systems. Of the 13 AQPs (AQP0 through AQP12) in the human body, four (AQPs 1, 3, 4, and 5) are expressed in the respiratory system. These channels are conventionally known for mediating transcellular fluid movements. Certain AQPs (aquaglyceroporins) have the capability to transport glycerol and potentially other solutes. There is an emerging body of literature unveiling the non-conventional roles of AQPs such as in cell proliferation and migration, gas permeation, signal potentiation, etc. Initial gene knock-out studies established a physiological role for lung AQPs, particularly AQP5, in maintaining homeostasis, by mediating fluid secretion from submucosal glands onto the airway surface liquid (ASL) lining. Subsequent studies have highlighted the functional significance of AQPs, particularly AQP1 and AQP5 in lung pathophysiology and diseases, including but not limited to chronic and acute lung injury, chronic obstructive pulmonary disease (COPD), other inflammatory lung conditions, and lung cancer. AQP1 has been suggested as a potential prognostic marker for malignant mesothelioma. Recent efforts are directed toward exploiting AQPs as targets for diagnosis, prevention, intervention, and/or treatment of various lung conditions. Emerging information on regulatory pathways and directed mechanistic research are posited to unravel novel strategies for these clinical implications. Future considerations should focus on development of AQP inhibitors, blockers, and modulators for therapeutic needs, and better understanding the role of lung-specific AQPs in inter-individual susceptibility to chronic lung diseases such as COPD and cancer.

Keywords: Acute lung injury; Aquaporins; Chronic obstructive pulmonary disease; Lung cancer; Lung inflammation; Lung pathophysiology; Regulation.

FIGURE 1.. Diagrammatic representation of transmembrane topology of aquaporin-1.

The arrangement depicts six transmembrane domains (M1 to M6), two loops which form the water pore on a subunit (loops B and E), and the regions implicated in gating (loop D) and activity modulation (C-terminus). The figure also illustrates regions blocked by the extracellular agents mercury (Hg) and tetraethylammonium ion (TEA⁺). Reproduced with permission from Yool et al 2010 [1].

FIGURE 2.. 3D structure model and tetrameric arrangement of AQP1.

A: AQP1 tetramer as viewed from the cell surface. One of the four monomers (bottom left) is shown in color to depict its parts: blue to represent the N-terminal and yellow to represent the C-terminal tandem repeat. The dashed line in red depicts the pseudo-2-fold axis relating the two halves of the monomer, and the small red square at the center depicts the 4-fold axis of the tetramer. The asterisk in each monomer represents the water pore. B: AQP1 monomer as viewed in the direction parallel to the membrane. H1-H6 denote membrane-spanning helices, A-E denote loops, and HB and HE denote the two pore helices formed by loops B and E, respectively. Reproduced with permission from Gonen and Walz 2006 [4]

FIGURE 3:. AQP expression in airways and lung compartments.

Upper Panel: Schematic diagram showing that mouse AQPs 1, 3, 4 and 5 are expressed in epithelia and endothelia throughout the nasopharyngeal cavity, airways (upper and lower), and alveolar compartment. Lower Panel: Schematic diagrams showing cellular expression patterns of AQPs in rat airways and lung tissues: A). Subcellular expression pattern of AQP5 in alveolar space. AQP5 (shown in red) is expressed in apical membrane of type 1 pneumocytes (P₁) but not expressed in type 2 pneumocytes (P₂) and AQP1 is expressed in the alveolar capillaries; B). Cellular expression pattern of AQPs in respiratory epithelial layer, depicting no expression in goblet cells, AQP3 expression in basal cells, AQP4 expression in surface columnar cells, and AQP1 in underlying capillaries and fibroblasts; C). Subcellular expression pattern of AQPs in secretory glands: AQP5 (red) in apical membrane of acinar cells, AQP3 (yellow) and 4 (blue) in basolateral domains of glandular cells of nasopharynx and conchus but not in salivary glands. Reproduced with permission the Upper panel image from Borok and Verkman 2002 [2] and the Lower panel images A, B, and C from Nielsen et al 1997 [10].