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. 2021 Jan 13;11(1):966.
doi: 10.1038/s41598-020-80005-w.

Molecular pathogenesis of rhegmatogenous retinal detachment

Tiina Öhman  1 , Lisa Gawriyski  1 , Sini Miettinen  1 , Markku Varjosalo  2 , Sirpa Loukovaara  3   4
Affiliations

Molecular pathogenesis of rhegmatogenous retinal detachment

Tiina Öhman et al. Sci Rep. .

Abstract

Rhegmatogenous retinal detachment (RRD) is an ophthalmic emergency, which usually requires prompt surgery to prevent further detachment and restore sensory function. Although several individual factors have been suggested, a systems level understanding of molecular pathomechanisms underlying this severe eye disorder is lacking. To address this gap in knowledge we performed the molecular level systems pathology analysis of the vitreous from 127 patients with RRD using state-of-the art quantitative mass spectrometry to identify the individual key proteins, as well as the biochemical pathways contributing to the development of the disease. RRD patients have specific vitreous proteome profiles compared to other diseases such as macular hole, pucker, or proliferative diabetic retinopathy eyes. Our data indicate that various mechanisms, including glycolysis, photoreceptor death, and Wnt and MAPK signaling, are activated during or after the RRD to promote retinal cell survival. In addition, platelet-mediated wound healing processes, cell adhesion molecules reorganization and apoptotic processes were detected during RRD progression or proliferative vitreoretinopathy formation. These findings improve the understanding of RRD pathogenesis, identify novel targets for treatment of this ophthalmic disease, and possibly affect the prognosis of eyes treated or operated upon due to RRD.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
RRD and patient characterization. (a) An optical coherence tomography scan of the right eye with acute-onset RRD of a 53-year old female patient reveals fovea-involving RRD (macula off) with edema in the outer retinal layers (right eye; central retinal thickness 594 µm at the fovea). Scale bar: 200 µm. RPE retinal pigment epithelium, T temporal, I inferior, N nasal, S superior. (b) Distribution of detached retinal area in studied RRD patients. Quadrant 0 = a large tear/rupture with starting (early-onset) local retinal detachment (RD), quadrant 1 = 25% of RD (covering one quadrant of retinal area), 2 quadrants = 50% of RD, 3 quadrants = 75% of RD and 4 quadrants = a total retinal detachment. (c) The demographics of the MH-Pucker, PDR-TRD and RRD patients, showing the distributions of the age (years) and vitreous protein concentration (mg/ml). The median is shown with a line and the mean with a dashed line.
Figure 2
Figure 2
SWATH-MS analysis of vitreous samples. (a) Vitreous samples were collected via vitrectomy and proteins were digested with trypsin. For spectral library generation, the resulting peptides were fractionated and analyzed using DDA mode. The spectral library built was then used to extract the peptide and the quantification information of the SWATH runs. Bioinformatics approaches were used to understand biological relevance of the differentially expressed proteins. (b) Cellular localization of the detected vitreal proteins were predicted using GO-Cellular Component terms with the DAVID bioinformatics tool. (c) Principal component analysis (PCA) and (d) hierarchical clustering analysis of the samples showed a clear separation of RRD and control posterior segment eye diseases (MH, Pucker and PDR-TRD). In the heat map all 1177 quantified proteins expression levels are shown as raw Z-score of the SWATH peak area of each sample.
Figure 3
Figure 3
Comparison between RRD and control posterior segment eye disease proteomes. The volcano plots of differentially expressed proteins between RRD and control MH-Pucker and PDR-TRD eye groups. P-value was set to match q-value < 0.1. The red dots indicate significantly differed proteins with q < 0.1 and FC > 2. Significantly upregulated proteins in the RRD samples were categorized by their biological processes.
Figure 4
Figure 4
Rhodopsin signaling. Representation of molecular steps in photoactivation (modified from Leskov et al. 2000). Step 1, A light photon activates rhodopsin (OPSD) by conformational change in the disk membrane. Step 2, activated rhodopsin makes contacts with G protein known as transducin (GNAT). Step 3, transducin dissociates from GDP and binds GTP, then the alpha subunit-GTP complex of transducin dissociates from the beta and gamma subunits. Step 4, the alpha subunit of transducin activates phosphodiesterase, also known as PDE6, by binding to one of two regulatory subunits of PDE and inhibits its activity. PDE6 hydrolyzes cGMP, forming GMP. Step 5, the intracellular concentration of cGMP decreases and therefore the CNGA1 cation channels close. Closure of the cation channels causes hyperpolarization of the cell due to the ongoing efflux of potassium ions. Abundance of the 8 proteins linked to rhodopsin signaling upregulated in RRD are shown as boxplots. **q < 0.1; *q < 0.5, ns non-significant differences.
Figure 5
Figure 5
RRD enriches glycolysis enzymes in the vitreous. Proteomics analysis showed 21 enriched protein in RRD involved in glycolysis. These RRD up-regulated proteins in the glycolysis pathway are highlighted in green and listed in the table. Fold changes marked in bold in table are significant (q < 0.1). Figure modified from WikiPathways (http://www.wikipathways.org).
Figure 6
Figure 6
Signaling proteins upregulated in RRD samples. Boxplots of differentially expressed protein in EMT-related signal transduction cascades: in (a) Wnt-signaling and (b) MAPK cascade. PCP planar cell polarity pathway. log2 Peak Area indicates protein abundance in vitreous. **p < 0.1; ns non-significant differences.
Figure 7
Figure 7
Protein abundances in acute RRD versus chronic RRD. (a) The volcano plots differentially expressed proteins between acute (area of retinal detachment less than one quadrant 0, n = 5) and chronic RRD (RRD with PVR, n = 8). The blue dots indicate significantly (p < 0.05) upregulated (FC < 2) proteins in chronic RRD and the red dots upregulated protein in acute RRD. Black dots indicate significantly differed proteins with FC < 2. (b) Progressive increase of protein abundance according to increasing RD quadrants. Proteins are classified according to whether they are associated with platelets activation (except TTHY), apoptosis or histones. Control samples (CTR) include MH, Pucker and PDR-TRD samples (n = 24). RRD patients with retinal detachment (RD) quadrant 0 and 1 were combined (n = 91), as well as quadrant 3 and 4 (n = 7). Mean protein intensity is displayed on log2-scale.
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