Anti-fibrotic activity of a rho-kinase inhibitor restores outflow function and intraocular pressure homeostasis

Li, Guorong; Lee, Chanyoung; Read, A. Thomas; Wang, Ke; Ha, Jung‐Min; Kuhn, Megan; Navarro, Iris; Cui, Jenny; Young, Katherine; Gorijavolu, Rahul; Sulchek, Todd; Kopczynski, Casey; Farsiu, Sina; Samples, John R.; Challa, Pratap; Ethier, C. Ross; Stamer, W. Daniel

doi:10.7554/elife.60831

Cited by 48 publications

(82 citation statements)

References 77 publications

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“…Thus, the Y-27632 ROCK inhibitor has been shown to significantly reduce actin stress fibres in the cytoskeleton of both TM and SC cell cultures [47]. Moreover, a recent study by Li et al (2021) reported a significant reduction in IOP in patients with ocular hypertension (OHT) and in a cohort of glucocorticoid (GC)-induced mouse model of OHT, following administration with netarsudil ROCK inhibitor [48]. Treatment with netarsudil also decreased the expression of fibrotic markers α-SMA and fibronectin, showing anti-fibrotic properties capable of restoring outflow facility function and reducing IOP in these mice [48].…”

Section: Discussionmentioning

confidence: 95%

“…Moreover, a recent study by Li et al (2021) reported a significant reduction in IOP in patients with ocular hypertension (OHT) and in a cohort of glucocorticoid (GC)-induced mouse model of OHT, following administration with netarsudil ROCK inhibitor [48]. Treatment with netarsudil also decreased the expression of fibrotic markers α-SMA and fibronectin, showing anti-fibrotic properties capable of restoring outflow facility function and reducing IOP in these mice [48]. This treatment shows promise for potential use as an anti-fibrotic glaucoma therapy.…”

Section: Discussionmentioning

confidence: 97%

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Fibrotic Changes to Schlemm’s Canal Endothelial Cells in Glaucoma

Kelly

Perkumas

Campbell

et al. 2021

IJMS

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Previous studies have shown that glaucomatous Schlemm’s canal endothelial cells (gSCECs) are stiffer and associated with reduced porosity and increased extracellular matrix (ECM) material compared to SCECs from healthy individuals. We hypothesised that Schlemm’s canal (SC) cell stiffening was a function of fibrotic changes occurring at the inner wall of SC in glaucoma. This study was performed in primary cell cultures isolated from the SC lumen of human donor eyes. RNA and protein quantification of both fibrotic and endothelial cell markers was carried out on both healthy and gSCECs. Functional assays to assess cell density, size, migration, proliferation, and mitochondrial function of these cells were also carried out. Indeed, we found that gSCECs deviate from typical endothelial cell characteristics and exhibit a more fibrotic phenotype. For example, gSCECs expressed significantly higher protein levels of the fibrotic markers α-SMA, collagen I-α1, and fibronectin, as well as significantly increased protein expression of TGFβ-2, the main driver of fibrosis, compared to healthy SCECs. Interestingly, we observed a significant increase in protein expression of endothelial marker VE-cadherin in gSCECs, compared to healthy SCECs. gSCECs also appeared to be significantly larger, and surprisingly proliferate and migrate at a significantly higher rate, as well as showing significantly reduced mitochondrial activity, compared to healthy SCECs.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 97%

Fibrotic Changes to Schlemm’s Canal Endothelial Cells in Glaucoma

Kelly

Perkumas

Campbell

et al. 2021

IJMS

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“…Several studies show altered MMP concentrations in AH from glaucomatous eyes compared to normal [ 26 , 27 ]. As demonstrated by various studies previously, the role of actin cytoskeleton-mediated TM contraction and ECM-mediated TM stiffness play important roles in regulating the AH drainage and IOP [ 28 , 29 , 30 ]. An increase in actin polymerization leads to increased cytoskeletal tension generated via actomyosin contraction.…”

Section: Introductionmentioning

confidence: 99%

“…This interplay between excessive actomyosin contractility and ECM stiffness results in increased AH outflow resistance ensuing in elevated IOP [ 10 , 29 , 31 ]. On the contrary, pharmacological agents that inhibit the fibrogenic activation, as well as decrease actin polymerization from lowering the actin-based cellular relaxation, aids in lowering the IOP [ 13 , 28 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

Cathepsin K Regulates Intraocular Pressure by Modulating Extracellular Matrix Remodeling and Actin-Bundling in the Trabecular Meshwork Outflow Pathway

Soundararajan

Ghag

Vuda

et al. 2021

Cells

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The homeostasis of extracellular matrix (ECM) and actin dynamics in the trabecular meshwork (TM) outflow pathway plays a critical role in intraocular pressure (IOP) regulation. We studied the role of cathepsin K (CTSK), a lysosomal cysteine protease and a potent collagenase, on ECM modulation and actin cytoskeleton rearrangements in the TM outflow pathway and the regulation of IOP. Initially, we found that CTSK was negatively regulated by pathological stressors known to elevate IOP. Further, inactivating CTSK using balicatib, a pharmacological cell-permeable inhibitor of CTSK, resulted in IOP elevation due to increased levels and excessive deposition of ECM-like collagen-1A in the TM outflow pathway. The loss of CTSK activity resulted in actin-bundling via fascin and vinculin reorganization and by inhibiting actin depolymerization via phospho-cofilin. Contrarily, constitutive expression of CTSK decreased ECM and increased actin depolymerization by decreasing phospho-cofilin, negatively regulated the availability of active TGFβ2, and reduced the levels of alpha-smooth muscle actin (αSMA), indicating an antifibrotic action of CTSK. In conclusion, these observations, for the first time, demonstrate the significance of CTSK in IOP regulation by maintaining the ECM homeostasis and actin cytoskeleton-mediated contractile properties of the TM outflow pathway.

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“…Thus, reducing the IOP is the primary mechanism of anti-glaucoma medications (beta-blockers, alpha-2 agonists, epinephrine derivatives, carbonic anhydrase inhibitors, prostaglandin analogs, and rho kinase inhibitors), which act by decreasing AH production, by increasing trabecular outflow facility or uveoscleral outflow, and/or by reducing episcleral venous pressure. 6 , 7 …”

Section: Introductionmentioning

confidence: 99%

HL3501, a Novel Selective A3 Adenosine Receptor Antagonist, Lowers Intraocular Pressure (IOP) in Animal Glaucoma Models

Kim

Yang

Kim

et al. 2022

Trans. Vis. Sci. Tech.

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Purpose The A3 adenosine receptor (A3AR) is a known therapeutic target for glaucoma treatment. In this study, we developed HL3501 and examined its selectivity profile and in vitro and in vivo effects. Methods For the rabbit model, intraocular pressure (IOP) was increased by laser photocoagulation of the trabecular meshwork (TM). The rabbits were then topically treated with HL3501, latanoprost, timolol, or vehicle for 3 weeks. For the mouse model, HL3501, latanoprost, or vehicle was administered following induced IOP elevation by dexamethasone (Dex). The IOP of all rabbits and mice was measured. Electroretinography was performed on both eyes of dark-adapted anesthetized mice on days 0 and 21. The mice's eyes were enucleated at the end of the treatment for immunofluorescence staining. Results HL3501 was highly specific to the A3AR and inhibitory of A3AR function. In the rabbit glaucoma model, HL3501 and latanoprost significantly decreased the IOP. In the Dex-treated mouse model, HL3501 and latanoprost significantly decreased the IOP and increased the b-wave amplitude as compared with the vehicle treatment. HL3501 and latanoprost also inhibited fibronectin and α-smooth muscle actin expression induced by Dex treatment. Conclusions HL3501 had effects similar to those of latanoprost in reducing ocular hypertension in animal models. HL3501 could be used as a novel approach to treat glaucoma. Translational Relevance HL3501 is a novel preclinical compound targeting the A3 adenosine receptor, which may also be a new treatment option to fill the unmet needs of many glaucoma patients.

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Anti-fibrotic activity of a rho-kinase inhibitor restores outflow function and intraocular pressure homeostasis

Cited by 48 publications

References 77 publications

Fibrotic Changes to Schlemm’s Canal Endothelial Cells in Glaucoma

Fibrotic Changes to Schlemm’s Canal Endothelial Cells in Glaucoma

Cathepsin K Regulates Intraocular Pressure by Modulating Extracellular Matrix Remodeling and Actin-Bundling in the Trabecular Meshwork Outflow Pathway

HL3501, a Novel Selective A3 Adenosine Receptor Antagonist, Lowers Intraocular Pressure (IOP) in Animal Glaucoma Models

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