Faculty Profiles - Koji Nishiguchi

Papers - Koji Nishiguchi

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Optic nerve head microcirculation in autosomal dominant optic atrophy and normal-tension glaucoma Reviewed

Noriko Himori, Hiroshi Kunikata, Maki Inoue, Takayuki Takeshita, Koji M. Nishiguchi, Toru Nakazawa

ACTA OPHTHALMOLOGICA Vol. 95 ( 8 ) page： e799 - e800 2017.12

Additive effects of genetic variants associated with intraocular pressure in primary open-angle glaucoma Reviewed

Fumihiko Mabuchi, Nakako Mabuchi, Yoichi Sakurada, Seigo Yoneyama, Kenji Kashiwagi, Hiroyuki Iijima, Zentaro Yamagata, Mitsuko Takamoto, Makoto Aihara, Takeshi Iwata, Kazuhide Kawase, Yukihiro Shiga, Koji M. Nishiguchi, Toru Nakazawa, Mineo Ozaki, Makoto Araie

PLOS ONE Vol. 12 ( 8 ) page： e0183709 2017.8

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

To investigate the association between the additive effects of genetic variants associated with intraocular pressure (IOP) and IOP, vertical cup-to-disc ratio (VCDR), and high tension glaucoma (HTG) or normal tension glaucoma (NTG) as phenotypic features of primary open-angle glaucoma (POAG), and to evaluate the clinical usefulness of the additive effects of IOP-related genetic variants for predicting IOP elevation, Japanese patients with HTG (n = 255) and NTG (n = 261) and 246 control subjects were genotyped for nine IOP-related genetic variants near CAV2, GAS7, GLCCI1/ICA1, ABCA1, ARHGEF12, FAM125B, FNDC3B, ABO, and PTPRJ/AGBL2. The total number of risk alleles of these genetic variants was calculated for each participant as a genetic risk score (GRS), and the association between the GRS and the maximum IOP, mean VCDR, and phenotype (HTG or NTG) of POAG was evaluated. As the GRS increased, the maximum IOP (P = 0.012) and VCDR (P = 0.010) significantly increased. The GRS (9.1 +/- 1.9) in patients with HTG was significantly higher (P = 0.011) than that (8.7 +/- 1.8) in control subjects. The patients with GRS >= 12 as a cut-off value had a 2.54 times higher (P = 0.0085) risk on HTG (maximum IOP >= 22mmHg) compared with all patients. The IOP-related GRS approach substantiated that the IOP and VCDR were increased by the additive effects of IOP-related genetic variants in POAG. The high IOP-related GRS in patients with HTG but not NTG shows that there are differences in the genetic background between HTG and NTG and supports the notion that the phenotype (HTG or NTG) in patients with POAG depends on the additive effects of IOP-related genetic variants. The above-mentioned cut-off value of IOP-related GRS may be clinically useful for predicting the risk of IOP elevation.

DOI： 10.1371/journal.pone.0183709

Web of Science

PubMed

Spatially and Temporally Regulated NRF2 Gene Therapy Using Mcp-1 Promoter in Retinal Ganglion Cell Injury Reviewed

Kosuke Fujita, Koji M. Nishiguchi, Yukihiro Shiga, Toru Nakazawa

MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT Vol. 5 page： 130 - 141 2017.6

Language：English Publishing type：Research paper (scientific journal) Publisher：CELL PRESS

Retinal ganglion cell degeneration triggered by axonal injury is believed to underlie many ocular diseases, including glaucoma and optic neuritis. In these diseases, retinal ganglion cells are affected unevenly, both spatially and temporally, such that healthy and unhealthy cells coexist in different patterns at different time points. Herein, we describe a temporally and spatially regulated adeno-associated virus gene therapy aiming to reduce undesired off-target effects on healthy retinal neurons. The Mcp-1 promoter previously shown to be activated in stressed retinal ganglion cells following murine optic nerve injury was combined with the neuroprotective intracellular transcription factor Nrf2. In this model, Mcp-1 promoter driven NRF2 expression targeting only stressed retinal ganglion cells showed efficacy equivalent to non-selective cytomegalovirus promoter-driven therapy for preventing cell death. However, cytomegalovirus promoter-mediated NRF2 transcription induced cellular stress responses and death of Brn3A-positive uninjured retinal ganglion cells. Such undesired effects were reduced substantially by adopting the Mcp-1 promoter. Combining a stress-responsive promoter and intracellular therapeutic gene is a versatile approach for specifically targeting cells at risk of degeneration. This strategy may be applicable to numerous chronic ocular and non-ocular conditions.

DOI： 10.1016/j.omtm.2017.04.003

Web of Science

PubMed

The neuroprotective effect of latanoprost acts via klotho-mediated suppression of calpain activation after optic nerve transection Reviewed

Kotaro Yamamoto, Kota Sato, Masayoshi Yukita, Masayuki Yasuda, Kazuko Omodaka, Morin Ryu, Kosuke Fujita, Koji M. Nishiguchi, Shigeki Machida, Toru Nakazawa

JOURNAL OF NEUROCHEMISTRY Vol. 140 ( 3 ) page： 495 - 508 2017.2

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

Latanoprost was first developed for use in glaucoma therapy as an ocular hypotensive agent targeting the prostaglandin F2 alpha (FP) receptor. Subsequently, latanoprost showed a neuroprotective effect, an additional pharmacological action. However, although it is well-known that latanoprost exerts an ocular hypotensive effect via the FP receptor, it is not known whether this is also true of its neuroprotective effect. Klotho was firstly identified as the gene linked to the suppression of aging phenotype: the defect of klotho gene in mice results aging phenotype such as hypokinesis, arteriosclerosis, and short lifespan. After that, the function of klotho was also reported to maintain calcium homeostasis and to exert a neuroprotective effect in various models of neurodegenerative disease. However, the function of klotho in eyes including retina is still poorly understood. Here, we show that klotho is a key factor underlying the neuroprotective effect of latanoprost during post-axotomy retinal ganglion cell (RGC) degeneration. Importantly, a quantitative RT-PCR gene expression analysis of klotho in sorted rat retinal cells revealed that the highest expression level of klotho in the retina was in the RGCs. Latanoprost acid, the biologically active form of latanoprost, inhibits post-traumatic calpain activation and concomitantly facilitates the expression and shedding of klotho in axotomized RGCs. This expression profile is a good match with the localization, not of the FP receptor, but of organic anion transporting polypeptide 2B1, known as a prostaglandin transporter, in the ocular tissue. Furthermore, an organic anion transporting polypeptide 2B1 inhibitor suppressed latanoprost acid-mediated klotho shedding exvivo, whereas an FP receptor antagonist did not. The klotho fragments shed from the RGCs reduced the intracellular level of reactive oxygen species, and a specific klotho inhibitor accelerated and increased RGC death after axotomy. We conclude that the shed klotho fragments might contribute to the attenuation of axonal injury-induced calpain activation and oxidative stress, thereby protecting RGCs from post-traumatic neuronal degeneration.

DOI： 10.1111/jnc.13902

Web of Science

PubMed

Brimonidine Enhances the Electrophysiological Response of Retinal Ganglion Cells through the Trk-MAPK/ERK and PI3K Pathways in Axotomized Eyes Reviewed

Masayoshi Yukita, Kazuko Omodaka, Shigeki Machida, Masayuki Yasuda, Kota Sato, Kazuichi Maruyama, Koji M. Nishiguchi, Toru Nakazawa

CURRENT EYE RESEARCH Vol. 42 ( 1 ) page： 125 - 133 2017.1

Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS INC

Purpose: To investigate changes in retinal ganglion cell (RGC) activity by measuring the positive scotopic threshold response (pSTR) of the electroretinogram (ERG) in axotomized eyes after brimonidine injection.Methods: In 50 adult Sprague-Dawley rats, the left eye was axotomized and injected with phosphate buffered saline (PBS) or brimonidine and the contralateral right eye was left untreated. Scotopic ERGs were recorded simultaneously from both eyes on days 1, 2, 3, 7, and 10 after the intravitreal injection, and the amplitude of the a- and b-waves and the pSTR were measured. Surviving RGCs in the flat-mounted retinas were counted 10 days after axotomy. In addition to brimonidine, K252a (an inhibitor of tyrosine kinase phosphorylation of the Trk receptors), U0126 (a MAPK/ERK kinase inhibitor), and LY294002 (phosphoinositide 3-kinases [PI3Ks]) were also injected intravitreally into the left eye, and ERGs were recorded using the same protocol.Results: The pSTR amplitude increased significantly in the axotomized eyes with brimonidine, to 122.9 5.0%, 161.8 +/- 8.3%, and 133.6 +/- 8.1% on days 1, 2, and 3 (P < 0.01), respectively, compared to the axotomized eyes treated with PBS (control). The increased pSTR amplitude returned to normal (103.6 +/- 6.7%) on day 7, although there were a greater number of surviving RGCs in the treatment groups than in the controls. The intravitreal injection of K252a, U0126, or LY294002 significantly attenuated the increase in pSTR induced by intravitreal brimonidine (P < 0.01).Conclusion: Intravitreal brimonidine enhanced the survival and electrophysiological activity of the RGCs in rats. The mechanism of this electrophysiological change may involve activation of the Trk-MAPK/ERK and Trk-PI3K signals.

DOI： 10.3109/02713683.2016.1153112

Web of Science

PubMed

Whole Genome Sequencing in Patients with Retinitis Pigmentosa

Nishiguchi, KM

ADVANCES IN VISION RESEARCH, VOL I: GENETIC EYE RESEARCH IN ASIA AND THE PACIFIC page： 83 - 91 2017

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Papers - Koji Nishiguchi