Abstract
Fluid shear modulates many biological properties. How shear mechanosensing occurs in the extracellular matrix (ECM) and is transduced into cytoskeletal change remains unknown. Cochlin is an ECM protein of unknown function. Our investigation using a comprehensive spectrum of cutting-edge techniques has resulted in following major findings: (1) over-expression and down-regulation of cochlin increase and decrease intraocular pressure (IOP), respectively. The overexpression was achieved in DBA/2J-Gpnmb+/SjJ using lentiviral vectors, down-regulation was achieved in glaucomatous DBA/2J mice using targeted disruption (cochlin-null mice) and also using lentiviral vector mediated shRNA against cochlin coding region; (2) reintroduction of cochlin in cochlin-null mice increases IOP; (3) injection of exogenous cochlin also increased IOP; (4) increasing perfusion rates increased cochlin multimerization, which reduced the rate of cochlin proteolysis by trypsin and proteinase K; The cochlin multimerization in response to shear stress suggests its potential mechanosensing. Taken together with previous studies, we show cochlin is involved in regulation of intraocular pressure in DBA/2J potentially through mechanosensing of the shear stress.
Highlights
Fluid shear is a mechanical stimulus experienced by cells and most organs involved with localized fluid flow
Cochlin Mediates intraocular pressure (IOP) Elevation in Mice Cochlin was overexpressed in DBA/2J-Gpnmb+/SjJ mice, which do not develop elevated IOP or glaucomatous neurodegeneration with age, to determine its role in IOP elevation
Mice injected with COCH transgene with IRES mediated GFP expressing (COCH-GFP) lentiviral vector into the anterior eye chamber showed a rise in IOP concomitant with cochlin expression, reaching a peak between 8–30 days
Summary
Fluid shear is a mechanical stimulus experienced by cells and most organs involved with localized fluid flow. Cellular mechanosensing is linked to cytoskeletal remodeling to respond appropriately to altered fluid shear dynamics in single and multicellular organisms [1]. IOP fluctuations likely alter cells of the trabecular meshwork (TM), a filter like structure in the anterior eye chamber, results in aqueous outflow dysregulation [4,5]. Regulation of ECM interstitial space is a major influencing factor for aqueous outflow resistance through the trabecular meshwork [7]. Stretch activated channels (SACs), such as TREK-1, function as mechanotransducers involved in pressure regulation [1,9]. TREK-1 mRNA is present in the TM, its role in pressure regulation has not been demonstrated nor has the involvement of cochlin in mechanosensing. We provide evidence here that cochlin is involved in IOP regulation
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