Renin-angiotensin system impairs macrophage lipid metabolism to promote age-related macular degeneration in mouse models.

Abstract	Metabolic syndrome, a condition involving obesity and hypertension, increases the risk of aging-associated diseases such as age-related macular degeneration (AMD). Here, we demonstrated that high-fat diet (HFD)-fed mice accumulated oxidized low-density lipoprotein (ox-LDL) in macrophages through the renin-angiotensin system (RAS). The ox-LDL-loaded macrophages were responsible for visual impairment in HFD mice along with a disorder of the retinal pigment epithelium (RPE), which is required for photoreceptor outer segment renewal. RAS repressed ELAVL1, which reduced PPARγ, impeding ABCA1 induction to levels that are sufficient to excrete overloaded cholesterol within the macrophages. The ox-LDL-loaded macrophages expressed inflammatory cytokines and attacked the RPE. An antihypertensive drug, angiotensin II type 1 receptor (AT1R) blocker, resolved the decompensation of lipid metabolism in the macrophages and reversed the RPE condition and visual function in HFD mice. AT1R signaling could be a future therapeutic target for macrophage-associated aging diseases, such as AMD.
Authors	Norihiro Nagai, Hirohiko Kawashima, Eriko Toda, Kohei Homma, Hideto Osada, Naymel A Guzman, Shinsuke Shibata, Yasuo Uchiyama, Hideyuki Okano, Kazuo Tsubota, Yoko Ozawa
Journal	Communications biology (Commun Biol) Vol. 3 Issue 1 Pg. 767 (12 09 2020) ISSN: 2399-3642 [Electronic] England
PMID	33299105 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	ATP Binding Cassette Transporter 1 Angiotensin II Type 1 Receptor Blockers Biomarkers Lipoproteins, LDL PPAR gamma Receptor, Angiotensin, Type 1 oxidized low density lipoprotein
Topics	ATP Binding Cassette Transporter 1 (metabolism) Angiotensin II Type 1 Receptor Blockers (pharmacology) Animals Biomarkers Diet, High-Fat Disease Models, Animal Disease Susceptibility Lipid Metabolism Lipoproteins, LDL (metabolism) Macrophages (immunology, metabolism, ultrastructure) Macular Degeneration (etiology, metabolism, pathology) Mice Models, Biological PPAR gamma (metabolism) Receptor, Angiotensin, Type 1 (metabolism) Renin-Angiotensin System (physiology) Retina (drug effects, metabolism, ultrastructure) Signal Transduction

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