Quantitative proteomics analysis of vitreous body from type 2 diabetic patients with proliferative diabetic retinopathy

Li, Jianqing; Lu, Qianyi; Lu, Peirong

doi:10.1186/s12886-018-0821-3

Cited by 26 publications

(23 citation statements)

References 42 publications

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“…These included deposition of C3d and MAC complex in the choriocapillaries of DR eyes and reduced level of glycosylphosphatidyl inositol-anchored inhibitors of complements such as CD55 and CD59 in the walls of retinal vessels of DR eyes, suggesting the role of the complement pathway in DR (27,28), although it is as yet unclear if this is a cause or an effect of prolonged diabetic insult. Though the vitreous proteome studies have detected several complement proteins such as C3, CFI, CFB, C4A, C4B, C2, C4BPA, CFD, and CFH in PDR subjects (29)(30)(31)(32), their expression levels are highly variable among different studies and do not explain their exact involvement in DR pathology as observed earlier in ROP and AMD. Also, the complement genes do not show any genetic association with the risk of DR as observed in AMD and ROP.…”

Section: Introductionmentioning

confidence: 90%

A Systematic Investigation on Complement Pathway Activation in Diabetic Retinopathy

et al. 2020

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The complement system plays a crucial role in retinal homeostasis. While the proteomic analysis of ocular tissues in diabetic retinopathy (DR) has shown the deposition of complement proteins, their exact role in the pathogenesis of DR is yet unclear. We performed a detailed investigation of the role of the complement system by evaluating the levels of major complement proteins including C3, C1q, C4b, Complement Factor B (CFB), and Complement Factor H (CFH) and their activated fragments from both the classical and alternative pathways in vitreous humor and serum samples from proliferative DR (PDR) patients and controls. Further, the expressions of complements and several other key pro-and anti-angiogenic genes in the serum and vitreous humor were analyzed in the blood samples of PDR and non-PDR (NPDR) patients along with controls without diabetes. We also assessed the pro-inflammatory cytokines and matrix metalloproteinases in the vitreous humor samples. There was a significant increase in C3 and its activated fragment C3bα' (110 kDa) along with a corresponding upregulation of CFH in the vitreous of PDR patients, which confirmed the increased activation of the alternative complement pathway in PDR. Likewise, a significant upregulation of angiogenic genes and downregulation of anti-angiogenic genes was seen in PDR and NPDR cases. Increased MMP9 activity and upregulation of inflammatory markers IL8 and sPECAM with a downregulation of anti-inflammatory marker IL-10 in PDR vitreous indicated the possible involvement of microglia in DR pathogenesis. Further, a significantly high C3 deposition in the capillary wall along with thickening of basement membranes and co-localization of CFH expression with CD11b +ve activated microglial cells in diabetic retina suggested microglia as a source of CFH in diabetic retina. The increased CFH levels could be a feedback mechanism for arresting excessive complement activation in DR eyes. A gradual increase of CFH and CD11b expression in retina with early to late changes in epiretinal membranes of DR patients indicated a major role for the alternative complement pathway in disease progression.

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Section: Introductionmentioning

confidence: 90%

A Systematic Investigation on Complement Pathway Activation in Diabetic Retinopathy

et al. 2020

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“…Therefore, timely expression of Kir 4.1 channels in Müller cells is necessary in the uptake of K + released by neurons in response to light and in siphoning these K + out to the vitreous and vasculature 45. We speculate that the effects of altered diurnal rhythm of Kir4.1 channels are multitude the Müller cells may remain10 consistently swollen throughout the course of diabetes resulting in an increase in oxidative stress and arachidonic acid metabolism; decreased light exposure (e.g., cataract) may lead to a decrease in potassium clearance in the vitreous; finally, change in vitreal composition in diabetes46,47 may independently affect the K + homeostasis and normal retinal function, contributing together to the pathogenesis of DR. Our study certainly paves a way for pursuing these possible pathogenic mechanisms of DR in future.…”

Section: Discussionmentioning

confidence: 93%

The Diurnal Rhythm of Insulin Receptor Substrate-1 (IRS-1) and Kir4.1 in Diabetes: Implications for a Clock Gene Bmal1

Luo

Xiao

Alex

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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PurposeDiabetes leads to the downregulation of the retinal Kir4.1 channels and Müller cell dysfunction. The insulin receptor substrate-1 (IRS-1) is a critical regulator of insulin signaling in Müller cells. Circadian rhythms play an integral role in normal physiology; however, diabetes leads to a circadian dysrhythmia. We hypothesize that diabetes will result in a circadian dysrhythmia of IRS-1 and Kir4.1 and disturbed clock gene function will have a critical role in regulating Kir4.1 channels.MethodsWe assessed a diurnal rhythm of retinal IRS-1 and Kir4.1 in db/db mice. The Kir4.1 function was evaluated using a whole-cell recording of Müller cells. The rat Müller cells (rMC-1) were used to undertake in vitro studies using a siRNA.ResultsThe IRS-1 exhibited a diurnal rhythm in control mice; however, with diabetes, this natural rhythm was lost. The Kir4.1 levels peaked and troughed at times similar to the IRS-1 rhythm. The IRS-1 silencing in the rMC-1 led to a decrease in Kir4.1 and BMAL1. The insulin treatment of retinal explants upregulated Kir4.1 possibly via upregulation of BMAL1 and phosphorylation of IRS-1 and Akt-1.ConclusionsOur studies highlight that IRS-1, by regulating BMAL1, is an important regulator of Kir4.1 in Müller cells and the dysfunctional signaling mediated by IRS-1 may be detrimental to Kir4.1.

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“…A comprehensive study done by Garcia et al , identified a significant increase in 42kDa fragment of C3 and CFB in PDR vitreous and found it to correlate with the mRNA expression in diabetic retina [22]. Additionally, various vitreous proteome studies in DR also identified the predominant deposition of complement proteins in PDR vitreous [20, 21, 26, 27] though exactly how complements are involved in PDR pathogenesis was not explored. Thus, here for the first time, we attempted a systematic evaluation of both alternative and classical pathwayof complement activation in PDR pathogenesis by analysing proteins of these two pathways in serum as well as in vitreous humor.…”

Section: Discussionmentioning

confidence: 99%

A systematic investigation on the involvement of complement pathway in diabetic retinopathy

Shahulhameed

Vishwakarma

Chhablani

et al. 2019

Preprint

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Background:Complement system play a crucial role in retinal homeostasis. Several proteomic studies have shown deposition of complement protein in ocular tissues from diabetic retinopathy, however, their exact involvement in pathogenesis of DR remains unclear. Methods:We evaluated major complement pathway proteins in the classical and alternative pathway including C1q, C4b, C3, CFB and CFH in vitreous humor and serum samples from PDR patients and controls by western blotting. Quantitative real time (QRT) PCR was done for PDR, NPDR and no-DM controls for correlating the expression of several key pro and anti -angiogenic genes with their correspondingprotein levels.Inflammation in the vitreous humor samples was assessed by ELISA and metalloproteinase activity measured by gelatin zymography. Glial activation and its association with complement activation in diabetic eyes was assessed by immunohistochemistry. Results:A significant increase in C3 proteins, its activated fragment C3bα' (110kDa) along with a concurrent up regulation of CFH was observed for PDR vitreous. QRT identified a significant upregulation of angiogenic genes and downregulation of antiangiogenic genes in PDR and NPDR cases. PDR vitreous had increased MMP9 activity and upregulation of inflammatory markers IL8, sPECAM and down regulation of anti-inflammatory marker IL-10. Increased C3 deposition and CFH upregulation were observed in DM retina. CFH was found co-localizing with CD11b+ve activated microglial cells in inner nuclear layer of DM retina. Conclusions:The present study confirms increased activation of alternative complement pathway in PDR. The colocalization of CFH in CD11b +ve cells further suggests microglia as a source of CFH in diabetic retina.Increased CFH levels could be a feedback mechanism for arresting excessive complement activation DR eyes. Introduction:Retina being an immune privileged organ, has its own unique immune regulatory mechanisms including retinal neurons and RPE, and immune defense mechanisms comprising microglial population and the complement system. The retinal immune defense mechanism get alerted with any kind of noxious signals and starts a series of inflammatory events as an adaptive response to restore the homeostatic balance[1].Low-level activation of the innate immune mechanisms, specifically complement system is required for preserving normal eye homeostasis and to maintain the retinal integrity while aging [2]. However, these protective mechanisms can cause detrimental consequences if the insults persist for a longer duration and lead to irreversible functional loss as evident from various neurodegenerative diseases such as Alzheimer's, Parkinson's, Amyotrophic lateral sclerosis, Age related macular degeneration etc [3].Beyond its role as an immune defense mechanism, studies have shown the involvement of complement system in various tissue remodeling process such as liver regeneration, synaptic pruning while development and also in retinal angiogenesis[4-6]. The role of complement in angiogenesis have prime imp...

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Quantitative proteomics analysis of vitreous body from type 2 diabetic patients with proliferative diabetic retinopathy

Cited by 26 publications

References 42 publications

A Systematic Investigation on Complement Pathway Activation in Diabetic Retinopathy

A Systematic Investigation on Complement Pathway Activation in Diabetic Retinopathy

The Diurnal Rhythm of Insulin Receptor Substrate-1 (IRS-1) and Kir4.1 in Diabetes: Implications for a Clock Gene Bmal1

A systematic investigation on the involvement of complement pathway in diabetic retinopathy

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