Netti Vanina, Cocca María Azul, Cutrera Nicolás, Molina Ponce Tomás, Ford Paula, Di Giusto Gisela, Capurro Claudia
Facultad de Ciencias Médicas, Departamento de Ciencias Fisiológicas, Laboratorio de Biomembranas, Universidad de Buenos Aires, Buenos Aires, Argentina.
Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Instituto de Fisiología y Biofísica Bernardo Houssay (IFIBIO Houssay), Paraguay 2155, 7Th Floor (1121), Ciudad Autónoma de Buenos Aires, Argentina.
Mol Neurobiol. 2025 Apr;62(4):4769-4784. doi: 10.1007/s12035-024-04595-6. Epub 2024 Nov 1.
During the intense neuronal activity in the retina, Müller cells are exposed to a hypotonic environment and activate a regulatory volume decrease (RVD) response, which depends on Aquaporin-4 (AQP4) and the calcium channel Transient Receptor Potential Vanilloid 4 (TRPV4). It was reported that Osteopontin (OPN), a cytokine and component of the extracellular matrix (ECM), may modulate the RVD of Müller cells. In other cell types, OPN participates in cell survival and migration, which Müller cells undergo to maintain retinal homeostasis. Therefore, the aim of this work was to study the putative crosstalk of OPN with AQP4 and/or TRPV4 in the main functions of Müller cells: RVD, morphology maintenance and migration. We used a human Müller cell line (MIO-M1) exposed to OPN and evaluated cell volume and osmotic permeability (P) during an osmotic swelling, AQP4 expression, cell morphology and migration. We observed that OPN induced a reduced P and RVD by downregulating AQP4 expression, which was prevented by TRPV4 inhibition. OPN also induced significant changes in cell morphology with an increased number of cytoplasmic projections. Finally, OPN reduced the migration of Müller cells, being this effect dependent on TRPV4. We propose that OPN affects water permeability and cell volume regulation of Müller cells by activating TRPV4 to reduce AQP4 expression. This represents a novel mechanism of regulation of water permeability by the ECM in Müller cells. Additionally, OPN-induced changes in morphology and migration of Müller cells may have an impact on retinal physiology.
在视网膜神经元活动剧烈时，米勒细胞会处于低渗环境并激活调节性容积减小（RVD）反应，该反应依赖于水通道蛋白4（AQP4）和钙通道瞬时受体电位香草酸受体4（TRPV4）。据报道，骨桥蛋白（OPN）作为一种细胞因子和细胞外基质（ECM）的成分，可能会调节米勒细胞的RVD。在其他细胞类型中，OPN参与细胞存活和迁移，而米勒细胞会经历这些过程以维持视网膜内环境稳定。因此，本研究的目的是探讨OPN与AQP4和/或TRPV4在米勒细胞的主要功能（RVD、形态维持和迁移）中可能存在的相互作用。我们使用了暴露于OPN的人米勒细胞系（MIO-M1），并在渗透性肿胀期间评估了细胞体积和渗透通透性（P）、AQP4表达、细胞形态和迁移情况。我们观察到，OPN通过下调AQP4表达诱导P和RVD降低，而TRPV4抑制可阻止这种降低。OPN还诱导细胞形态发生显著变化，细胞质突起数量增加。最后，OPN降低了米勒细胞的迁移，这种效应依赖于TRPV4。我们提出，OPN通过激活TRPV4以降低AQP4表达来影响米勒细胞的水通透性和细胞体积调节。这代表了ECM在米勒细胞中调节水通透性的一种新机制。此外，OPN诱导的米勒细胞形态和迁移变化可能会对视网膜生理学产生影响。
