title: The neuroprotective effect of latanoprost acts via klotho-mediated suppression of calpain activation after optic nerve transection.
abstract: 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.
authors.affiliation: Department of Ophthalmology, Tohoku University Graduate School of Medicine, Miyagi, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Department of Ophthalmology, Tohoku University Graduate School of Medicine, Miyagi, Japan.|Department of Ophthalmic Imaging and Information Analytics, Tohoku University Graduate School of Medicine, Miyagi, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Sato
authors.affiliation: Department of Ophthalmology, Tohoku University Graduate School of Medicine, Miyagi, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Yukita
authors.affiliation: Department of Ophthalmology, Tohoku University Graduate School of Medicine, Miyagi, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yasuda
authors.affiliation: Department of Ophthalmology, Tohoku University Graduate School of Medicine, Miyagi, Japan.|Department of Ophthalmic Imaging and Information Analytics, Tohoku University Graduate School of Medicine, Miyagi, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Omodaka
authors.affiliation: Department of Ophthalmology, Tohoku University Graduate School of Medicine, Miyagi, Japan.
authors.forename: Morin
authors.initials: M
authors.lastname: Ryu
authors.affiliation: Department of Retinal Disease Control, Tohoku University Graduate School of Medicine, Miyagi, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Fujita
authors.affiliation: Department of Advanced Ophthalmic Medicine, Tohoku University Graduate School of Medicine, Miyagi, Japan.
authors.forename: Koji M
authors.initials: KM
authors.lastname: Nishiguchi
authors.affiliation: Department of Ophthalmology, Dokkyo Medical University Koshigaya Hospital, Saitama, Japan.|Department of Ophthalmology, Iwate Medical University School of Medicine, Iwate, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Machida
authors.affiliation: Department of Ophthalmology, Tohoku University Graduate School of Medicine, Miyagi, Japan.|Department of Ophthalmic Imaging and Information Analytics, Tohoku University Graduate School of Medicine, Miyagi, Japan.|Department of Retinal Disease Control, Tohoku University Graduate School of Medicine, Miyagi, Japan.|Department of Advanced Ophthalmic Medicine, Tohoku University Graduate School of Medicine, Miyagi, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Nakazawa
mesh_terms: D000818:Animals; D002154:Calpain / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005966:Glucuronidase / Q000096:biosynthesis*; D006801:Humans; D000090265:Klotho Proteins; D000077338:Latanoprost; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D020221:Optic Nerve Injuries / Q000188:drug therapy* / Q000378:metabolism*; D011461:Prostaglandins F, Synthetic / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D018696:Neuroprotective Agents; D011461:Prostaglandins F, Synthetic; D000077338:Latanoprost; D005966:Glucuronidase; D000090265:Klotho Proteins; D002154:Calpain
keywords: calpain; glaucoma; klotho; latanoprost