α-Klotho prevents diabetic retinopathy by reversing the senescence of macrophages

作者：Qingbo Li, Pei‐Yu Wang, Yi Gong, Manhong Xu, Manqiao Wang, Rong Luan, Juping Liu, Xiaorong Li, Yan Shao · 发表于：Cell Communication and Signaling · 年份：2024 · DOI：10.1186/s12964-024-01838-w · 被引用次数：26 · 研究领域：Parathyroid Disorders and Treatments、Chronic Kidney Disease and Diabetes、Retinal Diseases and Treatments

BACKGROUND: 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 as an important risk factor for DR 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 (PDR) despite the occurrence of neovascularization and fibrosis (M2 activation). α-Klotho (KL) was originally discovered as a soluble anti-aging factor, which is mainly expressed in kidney tubular epithelium, choroid plexus in the brain and secreted in the blood. However, the role of KL in DR pathophysiology has not been previously reported. METHODS: mice were injected intravitreally with or without soluble KL protein from P8 to P15. The retinal structure and function were analyzed by electroretinogram and optical coherence tomography. The neovascular lesions were analyzed by retinal flat mount and RPE flat mount. The senescence markers, macrophage morphology, and KL expression levels were detected by immunofluorescence staining. A cell model was constructed using RAW264.7 cells stimulated by 4-hydroxynonenal (4HNE) and transfected with or without KL adenovirus. The senescence-associated secretory phenotypes were detected by qRT-PCR. Senescence was detected by SA-β-Gal staining. Serum, aqu...