TY - JOUR
T1 - The neuroprotective effect of latanoprost acts via klotho-mediated suppression of calpain activation after optic nerve transection
AU - Yamamoto, Kotaro
AU - Sato, Kota
AU - Yukita, Masayoshi
AU - Yasuda, Masayuki
AU - Omodaka, Kazuko
AU - Ryu, Morin
AU - Fujita, Kosuke
AU - Nishiguchi, Koji M.
AU - Machida, Shigeki
AU - Nakazawa, Toru
N1 - Funding Information:
This study was supported by grants from Pfizer, Inc. (WS2252097) and by a Grant-in-Aid from the Ministry of Education, Science and Technology of Japan (K.S. 26893019 and 15K20247, K.O. 15H06041, M. R. 25462749, T.N. 22689045 and 26670751). There is a conflict of interest. We thank Mr. Tim Hilts for reviewing and editing the language of the manuscript, Ms. Natsumi Konno, Ms. Junko Sato, and Ms. Kanako Sakai for the technical assistance. We also thank the Biomedical Research Core of Tohoku University Graduate School of Medicine for technical support. Authors thank Dr. Jun Kosaka (Okayama University) for gift of C38 antibody. All experiments were conducted in compliance with the ARRIVE guidelines.
Publisher Copyright:
� 2016 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry
PY - 2017/2/1
Y1 - 2017/2/1
N2 - Latanoprost was first developed for use in glaucoma therapy as an ocular hypotensive agent targeting the prostaglandin F2α (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 ex�vivo, 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. (Figure presented.).
AB - Latanoprost was first developed for use in glaucoma therapy as an ocular hypotensive agent targeting the prostaglandin F2α (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 ex�vivo, 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. (Figure presented.).
KW - calpain
KW - glaucoma
KW - klotho
KW - latanoprost
UR - http://www.scopus.com/inward/record.url?scp=85007384054&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85007384054&partnerID=8YFLogxK
U2 - 10.1111/jnc.13902
DO - 10.1111/jnc.13902
M3 - Article
C2 - 27859240
AN - SCOPUS:85007384054
VL - 140
SP - 495
EP - 508
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
SN - 0022-3042
IS - 3
ER -