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RKI-1447, a Rho kinase inhibitor, causes ocular hypotension, actin stress fiber disruption, and increased phagocytosis

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Abstract

Purpose

This study investigated the hypotensive effect of RKI-1447, a Rho kinase inhibitor, in a porcine ex vivo pigmentary glaucoma model.

Methods

Twenty-eight porcine anterior chambers were perfused with medium supplemented with 1.67 × 107 pigment particles/ml for 48 h before treatment with RKI-1447 (n = 16) or vehicle control (n = 12). Intraocular pressure (IOP) was recorded and outflow facility was calculated. Primary trabecular meshwork cells were exposed to RKI-1447 or vehicle control; effects on the cytoskeleton, motility, and phagocytosis were evaluated.

Result

Compared to baseline, the perfusion of pigment caused a significant increase in IOP in the RKI-1447 group (P = 0.003) at 48 h. Subsequent treatment with RKI-1447 significantly reduced IOP from 20.14 ± 2.59 to 13.38 ± 0.91 mmHg (P = 0.02). Pigment perfusion reduced the outflow facility from 0.27 ± 0.03 at baseline to 0.18 ± 0.02 at 48 h (P < 0.001). This was partially reversed with RKI-1447. RKI-1447 caused no apparent histological changes in the micro- or macroscopic TM appearance. RKI-1447-treated primary TM cells showed significant disruption of the actin cytoskeleton both in the presence and absence of pigment (P < 0.001) but no effect on TM migration was observed. Pigment-treated TM cells exhibited a reduction in TM phagocytosis, which RKI-1447 reversed.

Conclusion

RKI-1447 significantly reduces IOP by disrupting TM stress fibers and increasing TM phagocytosis. These features may make it useful for the treatment of secondary glaucomas with an increased phagocytic load.

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Funding

We acknowledge support from K08-EY022737 (NAL), from NIH CORE Grant P30 EY08098 to the Department of Ophthalmology, from the Initiative to Cure Glaucoma of the Eye and Ear Foundation of Pittsburgh (NAL), the Wiegand Fellowship (YD), and an unrestricted grant from the Research to Prevent Blindness, New York, NY, an unrestricted grant from the Third Xiangya Hospital of Central South University for studying at the University of Pittsburgh (CW).

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Authors and Affiliations

  1. Department of Ophthalmology, University of Pittsburgh School of Medicine, 203 Lothrop St, Suite 819, Pittsburgh, PA, 15213, USA

    Yalong Dang, Chao Wang, Priyal Shah, Susannah Waxman, Ralitsa T. Loewen & Nils A. Loewen

  2. Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China

    Chao Wang

  3. Institute of Ophthalmology and Visual Science, Rutgers New Jersey Medical School, Newark, NJ, USA

    Priyal Shah

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  1. Yalong Dang
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Correspondence to Nils A. Loewen.

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This article does not contain any studies with human participants or animals performed by any of the authors. No animals were sacrificed for the purpose of doing research. An approval by an ethics committee or Institutional Animal Care and Use Committee was not required.

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Dang, Y., Wang, C., Shah, P. et al. RKI-1447, a Rho kinase inhibitor, causes ocular hypotension, actin stress fiber disruption, and increased phagocytosis. Graefes Arch Clin Exp Ophthalmol 257, 101–109 (2019). https://doi.org/10.1007/s00417-018-4175-6

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