Research Paper Volume 13, Issue 17 pp 21547—21570
HSP90 acts as a senomorphic target in senescent retinal pigmental epithelial cells
- 1 The Division of Ophthalmology and Vision Science, Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- 2 The jointed National Laboratory of Antibody Drug Engineering, Department of Cell Biology and Genetics, The College of Basic Medical Science of Henan University, Kaifeng, China
- 3 Kaifeng Key laboratory of Cataracts and Myopia, Eye Disease Institute, Kaifeng Central Hospital, Kaifeng, China
- 4 Department of Medical Genetics and Cell Biology, School of Basic Medical Sciences, Zhengzhou University, Henan 450001, China
Received: May 5, 2021 Accepted: August 14, 2021 Published: September 8, 2021
https://doi.org/10.18632/aging.203496How to Cite
Copyright: © 2021 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
The senescence of retinal pigment epithelial (RPE) cells is associated with age-related macular degeneration (AMD), a leading cause of blindness in the world. HSP90 is a predominant chaperone that regulates cellular homeostasis under divergent physio-pathological conditions including senescence. However, the role of HSP90 in senescent RPE cells still remains unclear. Here, we reported that HSP90 acts as a senomorphic target of senescent RPE cells in vitro. Using H2O2-induced senescent ARPE-19 cells and replicative senescent primary RPE cells from rhesus monkey, we found that HSP90 upregulates the expression of IKKα, and HIF1α in senescent ARPE-19 cells and subsequently controls the induction of distinct senescence-associated inflammatory factors. Senescent ARPE-19 cells are more resistant to the cytotoxic HSP90 inhibitor IPI504 (IC50 = 36.78 μM) when compared to normal ARPE-19 cells (IC50 = 6.16 μM). Administration of IPI504 at 0.5–5 μM can significantly inhibit the induction of IL-1β, IL-6, IL-8, MCP-1 and VEGFA in senescent ARPE-19 and the senescence-mediated migration of retinal capillary endothelial cells in vitro. In addition, we found that inhibition of HSP90 by IPI504 reduces SA-β-Gal’s protein expression and enzyme activity in a dose-dependent manner. HSP90 interacts with and regulates SA-β-Gal protein stabilization in senescent ARPE-19 cells. Taken together, these results suggest that HSP90 regulates the SASP and SA-β-Gal activity in senescent RPE cells through associating with distinctive mechanism including NF-κB, HIF1α and lysosomal SA-β-Gal. HSP90 inhibitors (e.g. IPI504) could be a promising senomorphic drug candidate for AMD intervention.