The HIF‐1α/p53/miRNA‐34a/Klotho axis in retinal pigment epithelial cells promotes subretinal fibrosis and exacerbates choroidal neovascularization

Abstract

Wet age‐related macular degeneration (wAMD), characterized by choroidal neovascularization (CNV), is a leading cause of irreversible vision loss among elderly people in developed nations. Subretinal fibrosis, mediated by epithelial‐mesenchymal transition (EMT) of retinal pigment epithelium (RPE) cells, leads to unsuccessful anti‐vascular endothelial growth factor (VEGF) agent treatments in CNV patients. Under hypoxic conditions, hypoxia‐inducible factor‐1α (HIF‐1α) increases the stability and activation of p53, which activates microRNA‐34a (miRNA‐34a) transcription to promote fibrosis. Additionally, Klotho is a target gene of miRNA‐34a that inhibits fibrosis. This study aimed to explore the role of the HIF‐1α/p53/miRNA‐34a/Klotho axis in subretinal fibrosis and CNV. Hypoxia‐induced HIF‐1α promoted p53 stability, phosphorylation and nuclear translocation in ARPE‐19 cells (a human RPE cell line). HIF‐1α‐dependent p53 activation up‐regulated miRNA‐34a expression in ARPE‐19 cells following hypoxia. Moreover, hypoxia‐induced p53‐dependent miRNA‐34a inhibited the expression of Klotho in ARPE‐19 cells. Additionally, the HIF‐1α/p53/miRNA‐34a/Klotho axis facilitated hypoxia‐induced EMT in ARPE‐19 cells. In vivo, blockade of the HIF‐1α/p53/miRNA‐34a/Klotho axis alleviated the formation of mouse laser‐induced CNV and subretinal fibrosis. In short, the HIF‐1α/p53/miRNA‐34a/Klotho axis in RPE cells promoted subretinal fibrosis, thus aggravating the formation of CNV.

Inhibition of hypoxia-inducible factors suppresses subretinal fibrosis

“…The accumulation of HIF-1α in response to transient hypoglycemia has also been suggested to worsen ocular conditions in diabetes (39). For the subretinal area, Xie et al demonstrated that the blockade of the HIF-1α/p53/miRNA-34a axis could reduce laser-induced CNV volumes and mitigate subretinal fibrosis (20), which is similar with our current findings. We also previously found that RPE- or neural retina-specific Hif1a cKO could suppress CNV volumes at the acute stage in a murine model of laser-induced CNV (23).…”

“…In patients with ischemic retinal diseases, HIF-1α and HIF-2α could promote neovascularization in the retina (34). Among HIFs, HIF-1α has been considered as a main pathologic sensor in the eye (12, 20). A HIF-1 antagonist acriflavine has been shown to suppress ocular neovascularization in murines (35, 36).…”

Exosome MiR‐21‐5p Upregulated by HIF‐1α Induces Adipose Stem Cell Differentiation to Promote Ectopic Bone Formation

“…Bone mesenchymal stem cells (BMSCs) secrete large amounts of exosomes and the exosomes can carry microRNAs and other growth factors to regulate bone formation in the bone remodeling microenvironment . MicroRNA is a non-coding RNA that regulates the expression of several osteogenic genes in organisms, the expression of which was regulated by HIF-1α (Ge et al, 2021;Luo et al, 2022;Xie et al, 2021). In recent years, exosomes have been increasingly used to promote wound healing, stimulate bone regeneration and osteogenic induction (Hu et al, 2023;Qin et al, 2016;Zha et al, 2021).…”

Orally-active, clinically-translatable senolytics restore α-Klotho in mice and humans

“…α-Klotho is a geroprotective factor that exerts anti-physiological stress effects 1 and protects against oxidative damage, hypoxia, and cytotoxic drugs. 2 , 3 Soluble α-Klotho is an endocrine protein that regulates multiple biological processes, including phosphate homeostasis, mineral metabolism, 4 and signaling by insulin-like growth factor 1 (IGF-1), 5 , 6 mammalian target of rapamycin (mTOR), 7 , 8 cyclic adenosine monophosphate (cAMP), 9 , 10 p53/ p21 CIP1, 11 , 12 and Wnt proteins. 2 , 13 , 14 α-Klotho is synthesized and secreted by the distal renal tubule and so is present in urine.…”