2. Academic Validation
  3. Elevated Angiotensin-II Levels Contribute to the Pathogenesis of Open-Angle Glaucoma Via Inducing the Expression of Fibrosis-Related Genes in Trabecular Meshwork Cells Through a ROS/NOX4/SMAD3 Axis

Elevated Angiotensin-II Levels Contribute to the Pathogenesis of Open-Angle Glaucoma Via Inducing the Expression of Fibrosis-Related Genes in Trabecular Meshwork Cells Through a ROS/NOX4/SMAD3 Axis

  • Cell Transplant. 2023 Jan-Dec;32:9636897231162526. doi: 10.1177/09636897231162526.
Haijun Li 1,  Huiling Cui 1,  Jing Ren 1,  Di Wang 1,  Rumeng Zhao 1,  Shichao Zhu 2,  Siqing Liu 3,  Xiaohui Liu 1,  Shuai Tian 4,  Yuanyuan Zhang 4,  Panpan Zhao 4,  Peng Li 5,  Rick F Thorne 4,  Shichao Duan 1
Affiliations

Affiliations

  • 1 Henan Provincial People's Hospital, Henan Eye Hospital, Henan Eye Institute, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, China.
  • 2 Department of Pharmacology, College of Pharmacy, Army Medical University, Chongqing, China.
  • 3 The Second Hospital of Tianjin Medical University, Tianjin Medical University, Tianjin, China.
  • 4 Translational Research Institute, Henan Provincial People's Hospital, Academy of Medical Science, Zhengzhou University, Zhengzhou, China.
  • 5 Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.
PMID: 36999649 DOI: 10.1177/09636897231162526
Abstract

Glaucoma including primary open-angle glaucoma (POAG) results from elevations in intraocular pressure (IOP). An eye-localized renin-angiotensin system (Ras) has been implicated in IOP regulation, although its mechanism of action and contribution to glaucoma is poorly understood. Here, we detected significant increases in the levels of angiotensin II (ANGII) in aqueous humor samples from POAG patients. Moreover, we determined that the concentrations of ANGII were positively correlated with IOP, suggesting a role for elevated ANGII levels in eye pathogenesis. Functional investigations demonstrated that ANGII induces the expression of fibrosis-related genes of transformed and primary human trabecular meshwork cells (HTMCs) through the transcriptional upregulation of key fibrotic genes. Parallel experiments using a murine periocular conjunctival fornix injection model confirmed that ANGII induces the expression of fibrosis-related genes in trabecular meshwork (TM) cells in vivo along with increasing IOP. ANGII was revealed to function through increasing the levels of Reactive Oxygen Species (ROS) via selectively upregulating NOX4, with NOX4 knockdown or inhibition with GLX351322 alleviating fibrotic changes induced by ANGII. We further show that ANGII activates SMAD3, with both GLX351322 and an inhibitor of SMAD3 (SIS3) decreasing the phosphorylation of SMAD3 and dampening the ANGII-induced increases in fibrotic proteins. Moreover, NOX4 and SMAD3 inhibitors also partially rescued the elevated IOP levels induced by ANGII. Our collective results therefore highlight ANGII as a biomarker and treatment target in POAG together with establishing a causal relationship between ANGII and up-regulation of the expression of fibrosis-related genes of TM cells via a NOX4/ROS axis in cooperation with TGFβ/SMAD3 signaling.

Keywords

ANGII; NOX4; ROS; Smad3; aqueous humor; fibrosis; trabecular meshwork.

Figures
Products