Osteopontin Regulates AQP4 Expression by TRPV4 Activation in Müller Cells: Implications for Retinal Homeostasis

Abstract

During the intense neuronal activity in the retina, Müller cells are exposed to a hypotonic environment and activate aregulatory volume decrease (RVD) response, which depends on Aquaporin-4 (AQP4) and the calcium channel TransientReceptor Potential Vanilloid 4 (TRPV4). It was reported that Osteopontin (OPN), a cytokine and component of theextracellular matrix (ECM), may modulate the RVD of Müller cells. In other cell types, OPN participates in cell survivaland migration, which Müller cells undergo to maintain retinal homeostasis. Therefore, the aim of this work was to study theputative crosstalk of OPN with AQP4 and/or TRPV4 in the main functions of Müller cells: RVD, morphology maintenanceand migration. We used a human Müller cell line (MIO-M1) exposed to OPN and evaluated cell volume and osmoticpermeability (Pf) during an osmotic swelling, AQP4 expression, cell morphology and migration. We observed that OPNinduced a reduced Pf and RVD by downregulating AQP4 expression, which was prevented by TRPV4 inhibition. OPN alsoinduced signifcant changes in cell morphology with an increased number of cytoplasmic projections. Finally, OPN reducedthe migration of Müller cells, being this efect dependent on TRPV4. We propose that OPN afects water permeability andcell volume regulation of Müller cells by activating TRPV4 to reduce AQP4 expression. This represents a novel mechanismof regulation of water permeability by the ECM in Müller cells. Additionally, OPN-induced changes in morphology andmigration of Müller cells may have an impact on retinal physiology.