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

被引：21

作者：

Nagai, Norihiro ^{[1
,2
]}

Kawashima, Hirohiko ^{[1
,2
]}

Toda, Eriko ^{[1
]}

Homma, Kohei ^{[1
]}

Osada, Hideto ^{[1
]}

Guzman, Naymel A. ^{[1
,2
]}

Shibata, Shinsuke ^{[3
]}

Uchiyama, Yasuo ^{[4
]}

Okano, Hideyuki ^{[3
]}

Tsubota, Kazuo ^{[2
]}

Ozawa, Yoko ^{[1
,2
,5
,6
]}

机构：

[1] Keio Univ, Dept Ophthalmol, Lab Retinal Cell Biol, Sch Med,Shinjuku Ku, 35 Shinanomachi, Tokyo 1608582, Japan

[2] Keio Univ, Dept Ophthalmol, Sch Med, Shinjuku Ku, 35 Shinanomachi, Tokyo 1608582, Japan

[3] Keio Univ, Dept Physiol, Sch Med, Shinjuku Ku, 35 Shinanomachi, Tokyo 1608582, Japan

[4] Juntendo Univ, Dept Cellular & Mol Neuropathol, Grad Sch Med, Bunkyo Ku, Tokyo 1130033, Japan

[5] St Lukes Int Hosp, Dept Ophthalmol, Chuo Ku, 9-1 Akashi Cho, Tokyo 1048560, Japan

[6] St Lukes Int Hosp, 9-1 Akashi Cho, Tokyo 1048560, Japan

来源：

COMMUNICATIONS BIOLOGY | 2020年 / 3卷 / 01期

关键词：

II TYPE-1 RECEPTOR; RETINAL-PIGMENT EPITHELIUM; ACTIVATED PROTEIN-KINASE; BETA MESSENGER-RNA; NLRP3; INFLAMMASOME; CHOROIDAL NEOVASCULARIZATION; CHOLESTEROL EFFLUX; MURINE MODEL; CARDIOVASCULAR-DISEASE; BASAL DEPOSITS;

D O I：

10.1038/s42003-020-01483-2

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 PPAR gamma, 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. Nagai et al. show that mice fed high-fat diet (HFD) accumulate oxidized low-density lipoprotein in macrophages through the renin-angiotensin system, which impairs visual function. They find that angiotensin II type 1 receptor (AT1R) improves the visual function of HFD mice, suggesting AT1R signaling as a potential therapeutic target for age-related macular degeneration.

引用

页数：15

共 113 条

[91] Lysosomes: Regulators of autophagy in the retinal pigmented epithelium [J].