α-Klotho Prevents Diabetic Retinopathy by Reversing the Senescence of Macrophages

Abstract

Abstract Diabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus (DM) and a significant cause of acquired blindness in the working-age population worldwide. Aging is considered an important risk factor for its development. Macrophages in aged mice bear typical M2 marker proteins but simultaneously express a pro-inflammatory factor profile. This may explain why the level of intraocular inflammation does not decrease during proliferative diabetic retinopathy despite the occurrence of neovascularization and fibrosis (M2 activation). Our studies demonstrate that senescent macrophages are involved in the pathogenic mechanism of DR for the first time. α-Klotho (KL) is a well-established longevity protein. However, the role of KL in DR pathophysiology has not been previously reported. In vivo diabetic mice models showed a strong protective effect of KL on retinal structure and function in conditions of DM. Furthermore, the data suggested that KL alleviates DM-induced retinal macrophage senescence by downregulating HECTD1 and decreasing IRS1 ubiquitination and degradation. These results show that modulation of KL expression is an exciting and viable target for DR.