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

Nagai, Norihiro; Kawashima, Hirohiko; Toda, Eriko; Homma, Kyoji; Osada, Hideto; Guzman, Naymel A.; Shibata, Shinsuke; Uchiyama, Yasuo; Okano, Hideyuki; Ohta, Michio; Ozawa, Yoko

doi:10.1038/s42003-020-01483-2

Cited by 17 publications

(19 citation statements)

References 113 publications

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“…ERG recording was performed as previously described 20 – 22 . Briefly, mice were dark-adapted for 12 h and placed under dim-red illumination until they were anesthetized.…”

Section: Methodsmentioning

confidence: 99%

ADIPOR1 deficiency-induced suppression of retinal ELOVL2 and docosahexaenoic acid levels during photoreceptor degeneration and visual loss

et al. 2021

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Lipid metabolism-related gene mutations can cause retinitis pigmentosa, a currently untreatable blinding disease resulting from progressive neurodegeneration of the retina. Here, we demonstrated the influence of adiponectin receptor 1 (ADIPOR1) deficiency in retinal neurodegeneration using Adipor1 knockout (KO) mice. Adipor1 mRNA was observed to be expressed in photoreceptors, predominately within the photoreceptor inner segment (PIS), and increased after birth during the development of the photoreceptor outer segments (POSs) where photons are received by the visual pigment, rhodopsin. At 3 weeks of age, visual function impairment, specifically photoreceptor dysfunction, as recorded by electroretinography (ERG), was evident in homozygous, but not heterozygous, Adipor1 KO mice. However, although photoreceptor loss was evident at 3 weeks of age and progressed until 10 weeks, the level of visual dysfunction was already substantial by 3 weeks, after which it was retained until 10 weeks of age. The rhodopsin mRNA levels had already decreased at 3 weeks, suggesting that reduced rhodopsin may have contributed to early visual loss. Moreover, inflammation and oxidative stress were induced in homozygous KO retinas. Prior to observation of photoreceptor loss via optical microscopy, electron microscopy revealed that POSs were present; however, they were misaligned and their lipid composition, including docosahexaenoic acid (DHA), which is critical in forming POSs, was impaired in the retina. Importantly, the expression of Elovl2, an elongase of very long chain fatty acids expressed in the PIS, was significantly reduced, and lipogenic genes, which are induced under conditions of reduced endogenous DHA synthesis, were increased in homozygous KO mice. The causal relationship between ADIPOR1 deficiency and Elovl2 repression, together with upregulation of lipogenic genes, was confirmed in vitro. Therefore, ADIPOR1 in the retina appears to be indispensable for ELOVL2 induction, which is likely required to supply sufficient DHA for appropriate photoreceptor function and survival.

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“…ERG recording was performed as previously described 20 – 22 . Briefly, mice were dark-adapted for 12 h and placed under dim-red illumination until they were anesthetized.…”

Section: Methodsmentioning

confidence: 99%

ADIPOR1 deficiency-induced suppression of retinal ELOVL2 and docosahexaenoic acid levels during photoreceptor degeneration and visual loss

et al. 2021

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“…Moreover, mitochondrial dysfunction is also deeply involved in AMD [ 2 , 3 ], which is caused by the RPE dysregulation through inflammatory signaling [ 15 , 16 ] and resulting epithelial-mesenchymal transition (EMT) [ 17 , 18 ]. However, the relationship between mitochondrial functions and EMT in the RPE is still obscure.…”

Section: Introductionmentioning

confidence: 99%

Taurine rescues mitochondria-related metabolic impairments in the patient-derived induced pluripotent stem cells and epithelial-mesenchymal transition in the retinal pigment epithelium

et al. 2021

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Mitochondria participate in various metabolic pathways, and their dysregulation results in multiple disorders, including aging-related diseases. However, the metabolic changes and mechanisms of mitochondrial disorders are not fully understood. Here, we found that induced pluripotent stem cells (iPSCs) from a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) showed attenuated proliferation and survival when glycolysis was inhibited. These deficits were rescued by taurine administration. Metabolomic analyses showed that the ratio of the reduced (GSH) to oxidized glutathione (GSSG) was decreased; whereas the levels of cysteine, a substrate of GSH, and oxidative stress markers were upregulated in MELAS iPSCs. Taurine normalized these changes, suggesting that MELAS iPSCs were affected by the oxidative stress and taurine reduced its influence. We also analyzed the retinal pigment epithelium (RPE) differentiated from MELAS iPSCs by using a three-dimensional culture system and found that it showed epithelial mesenchymal transition (EMT), which was suppressed by taurine. Therefore, mitochondrial dysfunction caused metabolic changes, accumulation of oxidative stress that depleted GSH, and EMT in the RPE that could be involved in retinal pathogenesis. Because all these phenomena were sensitive to taurine treatment, we conclude that administration of taurine may be a potential new therapeutic approach for mitochondria-related retinal diseases.

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“…Montserrat-De La Paz et al found that oxidative stress and chronic inflammation were induced in RPE cells exposed to dietary fat, particularly SFA [24]. In animal experiments, Nagai et al demonstrated that high-fat diet-fed mice accumulate abnormal lipid deposition in the RPE, resulting in visual impairment, and have been used as an AMD model [25].…”

Section: Discussionmentioning

confidence: 99%

Association of Dietary Nutrient Intake with Early Age-Related Macular Degeneration in Japanese-Americans

et al. 2021

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Lifestyle factors may be associated with the development of age-related macular degeneration (AMD), in addition to demographic and genetic factors. The purpose of this cross-sectional study is to elucidate the association between nutrient intake and AMD in the Japanese-American population living in Los Angeles. We conducted a medical survey of Japanese immigrants and their descendants living in Los Angeles, including interviews on dietary habits, fundus photography, and physical examinations. Participants were classified into early AMD and control groups on the basis of fundus photographic findings. Consequently, among the 555 participants, 111 (20.0%) were diagnosed with early AMD. There were no late-stage AMD participants. Multivariate logistic regression analysis showed that the intake of animal fat and saturated fatty acids (SFA) was positively associated with early AMD (P for trend = 0.01 for animal fat, P for trend = 0.02 for SFA), and the intake of vegetable fat, total carbohydrate, simple carbohydrate, sugar, and fructose was inversely associated with early AMD (P for trend = 0.04 for vegetable fat, P for trend = 0.046 for carbohydrate, P for trend = 0.03 for simple carbohydrate, P for trend = 0.046 for sugar, P for trend = 0.02). Our findings suggest that excessive animal fat and SFA intake increases the risk for early AMD in Japanese-Americans whose lifestyles have been westernized.

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

Cited by 17 publications

References 113 publications

ADIPOR1 deficiency-induced suppression of retinal ELOVL2 and docosahexaenoic acid levels during photoreceptor degeneration and visual loss

ADIPOR1 deficiency-induced suppression of retinal ELOVL2 and docosahexaenoic acid levels during photoreceptor degeneration and visual loss

Taurine rescues mitochondria-related metabolic impairments in the patient-derived induced pluripotent stem cells and epithelial-mesenchymal transition in the retinal pigment epithelium

Association of Dietary Nutrient Intake with Early Age-Related Macular Degeneration in Japanese-Americans

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