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Subsequently, latanoprost showed a neuroprotective effect, an additional pharmacological action. However, although it is well\u2010known that latanoprost exerts an ocular hypotensive effect via the <jats:styled-content style=\"fixed-case\">FP<\/jats:styled-content> 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\u2010axotomy retinal ganglion cell (<jats:styled-content style=\"fixed-case\">RGC<\/jats:styled-content>) degeneration. Importantly, a quantitative <jats:styled-content style=\"fixed-case\">RT<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">PCR<\/jats:styled-content> gene expression analysis of <jats:italic>klotho<\/jats:italic> in sorted rat retinal cells revealed that the highest expression level of <jats:italic>klotho<\/jats:italic> in the retina was in the <jats:styled-content style=\"fixed-case\">RGC<\/jats:styled-content>s. Latanoprost acid, the biologically active form of latanoprost, inhibits post\u2010traumatic calpain activation and concomitantly facilitates the expression and shedding of klotho in axotomized <jats:styled-content style=\"fixed-case\">RGC<\/jats:styled-content>s. This expression profile is a good match with the localization, not of the <jats:styled-content style=\"fixed-case\">FP<\/jats:styled-content> 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\u2010mediated klotho shedding <jats:italic>ex\u00a0vivo<\/jats:italic>, whereas an <jats:styled-content style=\"fixed-case\">FP<\/jats:styled-content> receptor antagonist did not. The klotho fragments shed from the <jats:styled-content style=\"fixed-case\">RGC<\/jats:styled-content>s reduced the intracellular level of reactive oxygen species, and a specific klotho inhibitor accelerated and increased <jats:styled-content style=\"fixed-case\">RGC<\/jats:styled-content> death after axotomy. We conclude that the shed klotho fragments might contribute to the attenuation of axonal injury\u2010induced calpain activation and oxidative stress, thereby protecting <jats:styled-content style=\"fixed-case\">RGC<\/jats:styled-content>s from post\u2010traumatic neuronal degeneration.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc13902-fig-0009-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.13902","type":"journal-article","created":{"date-parts":[[2016,11,16]],"date-time":"2016-11-16T19:05:58Z","timestamp":1479323158000},"page":"495-508","source":"Crossref","is-referenced-by-count":21,"title":["The neuroprotective effect of latanoprost acts via klotho\u2010mediated suppression of calpain activation after optic nerve transection"],"prefix":"10.1111","volume":"140","author":[{"given":"Kotaro","family":"Yamamoto","sequence":"first","affiliation":[{"name":"Department of Ophthalmology Tohoku University Graduate School of Medicine Miyagi Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kota","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Tohoku University Graduate School of Medicine Miyagi Japan"},{"name":"Department of Ophthalmic Imaging and Information Analytics Tohoku University Graduate School of Medicine Miyagi Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masayoshi","family":"Yukita","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Tohoku University Graduate School of Medicine Miyagi 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