Role of Aquaporin-4 as an osmosensor in Retinal Müller cells: Implications in the physiopathology of Neuromyelitis Optica Spectrum Disorder.

JUAN FERNANDEZ; PAULA FORD; VANINA NETTI; GISELA DI GIUSTO; CAPURRO CLAUDIA; GARCIA-MIRANDA G; MIRIAM ECHEVARRIA

Congreso; SCHCF + ALACF 2020 joint meeting; 2020

Role of Aquaporin-4 as an osmosensor in Retinal Müller cells: Implications in the physiopathology of NeuromyelitisOptica Spectrum DisorderVanina Netti1, Juan Fernández1, Pablo García-Miranda2, Gisela Di Giusto1, Paula Ford1, Miriam Echevarría2, ClaudiaCapurro1(1) Laboratorio de Biomembranas, Instituto de Fisiología y Biofísica Bernardo Houssay (IFIBIO, UBA-CONICET), Facultadde Medicina, Universidad de Buenos Aires, Paraguay 2155, Buenos Aires, Argentina.(2) Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Av. ManuelSiurot s/n, Seville, Spain.Aquaporin-4 (AQP4) is the most abundant water channel expressed in the nervous system. Within the retina, AQP4 ismainly expressed in glial Müller cells, which control extracellular homeostasis. These cells regulate swelling, occurringbecause of the intense neuronal activity, by a regulatory volume decrease (RVD) mechanism which depends on the effluxof solutes and water through AQP4. AQP4 is also the target of autoantibody AQP4-IgG present in the sera of patientswith Neuromyelitis Optica Spectrum Disorder (NMOSD), a severe demyelinating autoimmune disease. Müller cellsrespond to injury by re-entering the cell cycle for tissue repair. It was reported that AQP4 modulates cell volume duringcell cycle progression to facilitate proliferation in astrocytes, but its involvement in Müller cells was not fully studied. Inthis work, we evaluated the role of AQP4 in Müller cells by two strategies: the use of the novel inhibitor TGN-020 andthe binding of AQP4-IgG to AQP4 in the human Müller cell line MIO-M1. We measured cell volume, osmotic waterpermeability (Pf) and intracellular Ca2+ levels during hypotonic shock and cell proliferation. AQP4 inhibition by TGN-020decreased Pf and RVD as expected, but also delayed hypotonicity-induced changes in Ca2+ kinetics, reinforcing the roleof AQP4 as an osmosensor in Müller cells. These cell volume changes may be involved in cell proliferation, which wasalso reduced by TGN-020. AQP4-IgG positive sera from NMOSD patients decreased AQP4 plasma membrane expression,which was associated to a reduction in Pf, RVD and the magnitude of intracellular Ca2+ increase. Cell proliferation wasalso slower in comparison to control sera. We propose that AQP4 inhibition or removal from the plasma membranereduces AQP4-mediated water permeability, altering cell proliferation. This is of particular importance in NMOSD, as thedecreased ability of Müller cells to proliferate may affect retinal tissue repair in vivo.Subsidio UBACYT 20020170100452BA, Universidad de Buenos Aires.This work was supported by grants from CAPES (Brazil), International Brain Research Organization and InternationalSociety for Neurochemistry.