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World J Diabetes. Jul 15, 2023; 14(7): 1027-1036
Published online Jul 15, 2023. doi: 10.4239/wjd.v14.i7.1027
Klotho: A new therapeutic target in diabetic retinopathy?
Alessandra Puddu, Davide Carlo Maggi
Alessandra Puddu, Davide Carlo Maggi, Department of Internal Medicine and Medical Specialties, University of Genova, Genova 16132, Italy
Author contributions: Puddu A and Maggi DC contributed equally to this work; Puddu A and Maggi DC contributed to the conception and design of the article, interpretation of relevant literature, wrote the manuscript, revised the manuscript; All authors approved the final version of the manuscript.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Alessandra Puddu, BSc, Technician, Department of Internal Medicine and Medical Specialties, University of Genova, Viale Benedetto XV 6, Genova 16132, Italy. alep100@hotmail.com
Received: February 16, 2023
Peer-review started: February 16, 2023
First decision: April 11, 2023
Revised: May 12, 2023
Accepted: May 22, 2023
Article in press: May 22, 2023
Published online: July 15, 2023
Abstract

Klotho (Kl) is considered an antiaging gene, mainly for the inhibition of the insulin-like growth factor-1 signaling. Kl exists as full-length transmembrane, which acts as co-receptor for fibroblast growth factor receptor, and in soluble forms (sKl). The sKl may exert pleiotropic effects on organs and tissues by regulating several pathways involved in the pathogenesis of diseases associated with oxidative and inflammatory state. In diabetic Patients, serum levels of Kl are significantly decreased compared to healthy subjects, and are related to duration of diabetes. In diabetic retinopathy (DR), one of the most common microvascular complications of type 2 diabetes, serum Kl levels are negatively correlated with progression of the disease. A lot of evidences showed that Kl regulates several mechanisms involved in maintaining homeostasis and functions of retinal cells, including phagocytosis, calcium signaling, secretion of vascular endothelial growth factor A (VEGF-A), maintenance of redox status, and melanin biosynthesis. Experimental data have been shown that Kl exerts positive effects on several mechanisms involved in onset and progression of DR. In particular, treatment with Kl: (1) Prevents apoptosis induced by oxidative stress in human retinal endothelial cells and in retinal pigment epithelium (RPE) cells; (2) reduces secretion of VEGF-A by RPE cells; and (3) decreases subretinal fibrosis and preserves autophagic activity. Therefore, Kl may become a novel biomarker and a good candidate for the treatment of DR.

Keywords: Klotho, Diabetic retinopathy, Retinal pigment epithelium, Vascular endothelial growth factor A, Epithelial to mesenchimal transition, Ocular neo-vascularization

Core Tip: In diabetic Patients, serum levels of Klotho (Kl) are significantly decreased compared to healthy subjects. Moreover, serum Kl levels are negatively correlated with worsening of diabetic retinopathy (DR). Several evidence suggests that retina homeostasis may be affected by altered expression of membrane Kl, as well by reduced levels of soluble Kl. In this review we focused on the role of Kl in DR, highlighting the importance of Kl in maintaining retinal homeostasis and its positive effects on several mechanisms involved in DR onset and progression. Therefore, Kl could be a novel biomarker and a good candidate for the treatment of DR.