Klotho: A new therapeutic target in diabetic retinopathy?

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

Figure 1

Positive effects of Klotho in diabetic retinopathy. VEGF-A: Vascular endothelial growth factor A.