Abstract: Ocular hypertension believed to result partly from increased contractile activity cell adhesive interactions and stiffness within the trabecular meshwork (TM) is a major risk factor for glaucoma a leading cause of blindness. However the identity of molecular mechanisms governing organization of actomyosin and cell adhesive interactions in the TM remains limited. Based on our previous findings in which proteomics analyses revealed elevated levels of septins including septin-9 in human TM cells treated with the ocular hypertensive agent dexamethasone here we evaluated the effects of septin-9 overexpression deficiency and pharmacological targeting in TM cells. These studies demonstrated a profound impact on actomyosin organization cell adhesion contraction and phagocytosis. Overexpression raised intraocular pressure (IOP) in mice while inhibition increased cell permeability. In addition we replicated a significant association between a common variant (rs9038) in SEPT9 with IOP in the Genetic Epidemiology Research on Adult Healthy and Aging (GERA) cohort. Collectively these data reveal a link between dysregulated septin cytoskeletal organization in the TM and increased IOP likely due to enhanced cell contraction adhesive interactions and fibrotic activity. This suggests that targeting the septin cytoskeleton could offer a novel approach for lowering IOP in patients with glaucoma.
https://insight.jci.org/articles/view/179468/pdf
https://insight.jci.org/articles/view/179468/pdf