HIF-1α accumulation in response to transient hypoglycemia may worsen diabetic eye disease

Guo, Chuanyu; Deshpande, Monika; Niu, Yueqi; Kachwala, Isha; Flores-Bellver, Miguel; Megarity, Haley; Nuse, Taylor; Babapoor-Farrokhran, Savalan; Ramada, Michael; Sanchez, Jaron Castillo; Inamdar, Neelay; Johnson, Thomas V.; Canto‐Soler, M. Valeria; Montaner, Silvia; Sodhi, Akrit

doi:10.1016/j.celrep.2022.111976

Cited by 21 publications

(16 citation statements)

References 45 publications

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“…To investigate this hypothesis, we first confirmed that the secretion of IFN-β into the culture medium of mouse RECs (mRECs) was increased following activation of STING by cGAMP compared with untreated controls ( Figure 6A ). We further conducted a retinal explant experiment ( 55 ) and found the levels of senescence-associated secretory phenotype (SASP) mediators, like HMGB1 and IL-1β, were high in the spent media from high glucose–exposed (HG-exposed, 25 mM D-glucose) WT retinal explants, compared with WT retinal explants cultured in presence of low glucose (LG, 5 mM D-glucose). However, HG-exposed STING -KO and STING GT retinal explants did not show such changes, indicating that STING might be involved in retinal cell senescence in diabetes ( Supplemental Figure 4 ).…”

Section: Resultsmentioning

confidence: 99%

“…Lastly, the IFN titer of the samples was determined by plotting the optical densities using a 4-parameter fit for the standard curve in GraphPad Prism 9 (version 9.3.1). The retinal explants from WT, STING -KO, and STING GT mice were cultured in presence or absence of LG or HG as explained above and in a previous report ( 55 ). The spent media from the cultures were analyzed by ELISA for HMGB1 (Novus Biologicals, NBP2-62767) and IL-1β (Invitrogen, BMS6002) using commercially available kits and following the manufacturer’s guidelines.…”

Section: Methodsmentioning

confidence: 99%

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Activated cGAS/STING signaling elicits endothelial cell senescence in early diabetic retinopathy

Ghosh¹,

Vaidya²,

Bammidi³

et al. 2023

JCI Insight

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Diabetic retinopathy (DR) is a leading cause of blindness in working-age adults and remains an important public health issue worldwide. Here we demonstrate that the expression of stimulator of interferon genes (STING) is increased in patients with DR and animal models of diabetic eye disease. STING has been previously shown to regulate cell senescence and inflammation, key contributors to the development and progression of DR. To investigate the mechanism whereby STING contributes to the pathogenesis of DR, diabetes was induced in STING -KO mice and STING GT (loss-of-function mutation) mice, and molecular alterations and pathological changes in the retina were characterized. We report that retinal endothelial cell senescence, inflammation, and capillary degeneration were all inhibited in STING -KO diabetic mice; these observations were independently corroborated in STING GT mice. These protective effects resulted from the reduction in TBK1, IRF3, and NF-κB phosphorylation in the absence of STING. Collectively, our results suggest that targeting STING may be an effective therapy for the early prevention and treatment of DR.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Activated cGAS/STING signaling elicits endothelial cell senescence in early diabetic retinopathy

Ghosh¹,

Vaidya²,

Bammidi³

et al. 2023

JCI Insight

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“…51 Fluctuations of blood glucose, particularly when a patient is outside of the ideal range, either hypoglycemic or hyperglycemic, are known to be a potential driving force for diabetic eye disease. 52 This type of data could be obtained with continuous glucose monitoring systems and may provide important information about individual differences. In addition, HbA1c provides no information about total hemoglobin and thus does not address the potential risk of ischemia that is conferred from other comorbidities such as anemia.…”

Section: Discussionmentioning

confidence: 99%

“…This metric provides no details about fluctuations in blood glucose over time, which is an advantage for reducing variability from meals and exercise during the day but a disadvantage for reporting only an average and not about the time within range 51 . Fluctuations of blood glucose, particularly when a patient is outside of the ideal range, either hypoglycemic or hyperglycemic, are known to be a potential driving force for diabetic eye disease 52 . This type of data could be obtained with continuous glucose monitoring systems and may provide important information about individual differences.…”

Section: Discussionmentioning

confidence: 99%

Clinically significant macular edema in an underserved population: Association with demographic factors and hemoglobin A1c

Parimi,

Elsner,

Gast

et al. 2024

Optom Vis Sci

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SIGNIFICANCE Suspected clinically significant macular edema (SCSME) from exudates differed among ethnic groups in our underserved population. African American and Asian subjects had higher prevalence than Hispanics and non-Hispanic Caucasians, from the same clinics. Men had higher prevalence than women. Highly elevated blood glucose was frequent and associated with SCSME. PURPOSE We investigated the association between the presence of SCSME from exudates and hemoglobin A1c (HbA1c), as well as demographic factors such as age, sex, and ethnic group. Our population was underserved diabetic patients from the same geographic locations. Ethnic groups were White Hispanic, non-Hispanic Caucasian, African American, and Asian, with a high proportion of underrepresented minorities. METHODS In a diabetic retinopathy screening study at four community clinics in Alameda County, California, nonmydriatic 45° color fundus images were collected from underserved diabetic subjects following the EyePACS imaging protocol. Images were analyzed for SCSME from exudates by two certified graders. Logistic regression assessed the association between SCSME from exudates and age, sex, ethnic group, and HbA1c. RESULTS Of 1997 subjects, 147 (7.36%) had SCSME from exudates. The mean ± standard deviation age was 53.4 ± 10.5 years. The mean ± standard deviation HbA1c level was 8.26 ± 2.04. Logistic regression analysis indicated a significant association between presence of SCSME from exudates and HbA1c levels (p<0.001), sex (p=0.027), and ethnicity (p=0.030). African Americans (odds ratio [OR], 1.63; 95% confidence interval [CI], 1.06 to 2.50; p=0.025) and Asians (OR, 1.63; 95% CI, 1.05 to 2.54; p=0.029) had a higher risk than Hispanics. After adjusting for ethnicity, sex, and age, the odds of developing SCSME from exudates increased by 26.5% with every 1% increase in HbA1c level (OR, 1.26; 95% CI, 1.18 to 1.36; p<0.001). CONCLUSIONS In our underserved population, many diabetic patients had very high HbA1c values. Ethnic background (African American > Asians > Hispanics), sex (male > female), and HbA1c level were strong indicators for identifying who is at increased risk of developing SCSME from exudates.

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“…A recently developed HIF inhibitor 32-134D (structurally different from acriflavine) was suggested to inhibit the accumulation of HIFs and normalize HIF-target gene expressions in mice and human retinal organoids (38). 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.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of hypoxia-inducible factors suppresses subretinal fibrosis

Shoda,

Lee,

Miwa

et al. 2023

Preprint

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Age-related macular degeneration (AMD) is a common cause of vision loss. The aggressive form of AMD is associated with ocular neovascularization and subretinal fibrosis, representing a responsive outcome against neovascularization mediated by epithelial-mesenchymal transition of retinal pigment epithelium cells. A failure of the current treatment (anti-vascular endothelial growth factor therapy) has also been attributed to the progression of subretinal fibrosis. Hypoxia-inducible factors (HIFs) increase gene expressions to promote fibrosis and neovascularization. HIFs act as a central pathway in the pathogenesis of AMD. HIF inhibitors may suppress ocular neovascularization. Nonetheless, further investigation is required to unravel the aspects of subretinal fibrosis. In this study, we used RPE-specific HIFs or von Hippel-Lindau (VHL, a regulator of HIFs) conditional knockout (cKO) mice, along with pharmacological HIF inhibitors, to demonstrate the suppression of subretinal fibrosis. Fibrosis was suppressed by treatments of HIF inhibitors, and similar suppressive effects were detected in RPE-specificHif1a/Hif2a-andHif1a-cKO mice. Promotive effects were observed in RPE-specificVhl-cKO mice, where fibrosis-mediated pathologic processes were evident. Marine products’ extracts and their component taurine suppressed fibrosis as HIF inhibitors. Our study shows critical roles of HIFs in the progression of fibrosis, linking them to the potential development of therapeutics for AMD.

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HIF-1α accumulation in response to transient hypoglycemia may worsen diabetic eye disease

Cited by 21 publications

References 45 publications

Activated cGAS/STING signaling elicits endothelial cell senescence in early diabetic retinopathy

Activated cGAS/STING signaling elicits endothelial cell senescence in early diabetic retinopathy

Clinically significant macular edema in an underserved population: Association with demographic factors and hemoglobin A1c

Inhibition of hypoxia-inducible factors suppresses subretinal fibrosis

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