Decreased MicroRNA-150 Exacerbates Neuronal Apoptosis in the Diabetic Retina

Yu, Fei; Ko, Michael L.; Ko, Gladys Y.-P.

doi:10.3390/biomedicines9091135

Cited by 6 publications

(14 citation statements)

References 51 publications

(84 reference statements)

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“…Retinal ganglion and amacrine cells are the first neurons in which hyperglycemia induces apoptosis ( 20 ). Photoreceptor cells in the diabetic retina also die through apoptosis and calpain activation ( 21 , 22 ). Several animal models have been developed to study the molecular basis of DR pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

A Novel Tree Shrew Model of Diabetic Retinopathy

et al. 2022

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Existing animal models with rod-dominant retinas have shown that hyperglycemia injures neurons, but it is not yet clearly understood how blue cone photoreceptors and retinal ganglion cells (RGCs) deteriorate in patients because of compromised insulin tolerance. In contrast, northern tree shrews (Tupaia Belangeri), one of the closest living relatives of primates, have a cone-dominant retina with short wave sensitivity (SWS) and long wave sensitivity (LWS) cones. Therefore, we injected animals with a single streptozotocin dose (175 mg/kg i.p.) to investigate whether sustained hyperglycemia models the features of human diabetic retinopathy (DR). We used the photopic electroretinogram (ERG) to measure the amplitudes of A and B waves and the photopic negative responses (PhNR) to evaluate cone and RGC function. Retinal flat mounts were prepared for immunohistochemical analysis to count the numbers of neurons with antibodies against cone opsins and RGC specific BRN3a proteins. The levels of the proteins TRIB3, ISR-1, and p-AKT/p-mTOR were measured with western blot. The results demonstrated that tree shrews manifested sustained hyperglycemia leading to a slight but significant loss of SWS cones (12%) and RGCs (20%) 16 weeks after streptozotocin injection. The loss of BRN3a-positive RGCs was also reflected by a 30% decline in BRN3a protein expression. These were accompanied by reduced ERG amplitudes and PhNRs. Importantly, the diabetic retinas demonstrated increased expression of TRIB3 and level of p-AKT/p-mTOR axis but reduced level of IRS-1 protein. Therefore, a new non-primate model of DR with SWS cone and RGC dysfunction lays the foundation to better understand retinal pathophysiology at the molecular level and opens an avenue for improving the research on the treatment of human eye diseases.

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Section: Introductionmentioning

confidence: 99%

A Novel Tree Shrew Model of Diabetic Retinopathy

et al. 2022

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“…We previously showed that miR-150 −/− -T2D mice have more severe inflammation in photoreceptors and exacerbated vascular degeneration compared with the WT-HFD mice [ 142 ]. Since the biological processes mediated by microRNAs and their targets are often tissue- and cell-type-dependent as stated earlier [ 152 , 195 ], after screening the top 30 predicted target genes of miR-150 [ 113 , 193 ] and identifying new bona fide targets that are pro-inflammatory [ 113 ], multiple transcription factors including the eukaryotic translation termination factor 1 ( Etf1 ), early growth response 1 ( Egr1 ), MYB proto-oncogene ( Myb ), and ETS-domain transcription factor 1 (Elk1) were found to be expressed in retinal photoreceptors and endothelial cells [ 196 ]. Downregulation of miR-150 correlates with an upregulation of Etf1 , Egr1 , Myb , and Elk1 and pro-inflammatory cytokines, while overexpression of miR-150 or knocking down any of these transfection factors decrease the expression of pro-inflammatory cytokines in cultured adipose B lymphocytes [ 113 ].…”

Section: Microrna-150 and Drmentioning

confidence: 99%

“…Using cultured murine photoreceptors treated with palmitic acid (PA) to mimic obesity-associated T2D, we found that PA elicited an increase of phosphorylated NF-ĸB (pP65), an inflammation marker, which persisted for 24 h and correlated with a persisting decrease of miR-150 and increase of Elk1 . However, PA elicited only temporary increases of Etf1 , Egr1 , or Myb , although these three transcription factors are direct downstream targets of miR-150 and expressed in the neural retina [ 196 ]. Overexpression of miR-150 or knocking down Elk1 not only decreased the expression of ELK1 (protein) but also relieved PA-induced increase of inflammation.…”

Section: Microrna-150 and Drmentioning

confidence: 99%

“…Deletion of miR-150 not only upregulated ELK1 but also cytoplasmic pELK1 S383 in photoreceptors. The miR-150 −/− mice with obesity-associated T2DR had further exacerbated retinal photoreceptor inflammation compared with the WT-T2DR mice, and the photoreceptor inflammation correlated with an increase of pELK1 S383 in the retinal outer nuclear layer [ 196 ]. The nuclear/cytoplasmic (N/C) ratio represents the cytoplasm-to-nucleus translocation of pELK1 S383 , and PA treatments increased the N/C ratio of pELK1 S383 in cultured photoreceptors, and knocking down Elk1 decreased nuclear pELK1 S383 and the N/C ratio of pELK1 S383 in PA-treated photoreceptors, which also correlated with the downregulation of pP65.…”

Section: Microrna-150 and Drmentioning

confidence: 99%

“…Hence, T2D-associated inflammation in photoreceptors was in part mediated by a decrease of miR-150 that caused an increase of nuclear pELK1 S383 and led to photoreceptor inflammation. Therefore, overexpression of miR-150 or knocking down of Elk1 may restrain the development of DR by mitigating the inflammation in the neural retina, especially in photoreceptors [ 196 ].…”

Section: Microrna-150 and Drmentioning

confidence: 99%

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MicroRNA-150 (miR-150) and Diabetic Retinopathy: Is miR-150 Only a Biomarker or Does It Contribute to Disease Progression?

Bayless

et al. 2022

IJMS

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Diabetic retinopathy (DR) is a chronic disease associated with diabetes mellitus and is a leading cause of visual impairment among the working population in the US. Clinically, DR has been diagnosed and treated as a vascular complication, but it adversely impacts both neural retina and retinal vasculature. Degeneration of retinal neurons and microvasculature manifests in the diabetic retina and early stages of DR. Retinal photoreceptors undergo apoptosis shortly after the onset of diabetes, which contributes to the retinal dysfunction and microvascular complications leading to vision impairment. Chronic inflammation is a hallmark of diabetes and a contributor to cell apoptosis, and retinal photoreceptors are a major source of intraocular inflammation that contributes to vascular abnormalities in diabetes. As the levels of microRNAs (miRs) are changed in the plasma and vitreous of diabetic patients, miRs have been suggested as biomarkers to determine the progression of diabetic ocular diseases, including DR. However, few miRs have been thoroughly investigated as contributors to the pathogenesis of DR. Among these miRs, miR-150 is downregulated in diabetic patients and is an endogenous suppressor of inflammation, apoptosis, and pathological angiogenesis. In this review, how miR-150 and its downstream targets contribute to diabetes-associated retinal degeneration and pathological angiogenesis in DR are discussed. Currently, there is no effective treatment to stop or reverse diabetes-caused neural and vascular degeneration in the retina. Understanding the molecular mechanism of the pathogenesis of DR may shed light for the future development of more effective treatments for DR and other diabetes-associated ocular diseases.

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