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Retinal proteome associated with bradykinin-induced edema.
Exp Eye Res 2019; 186:107744EE

Abstract

The plasma kallikrein-stimulated generation of bradykinin (BK) has been implicated in diabetic macular edema (DME). This study characterizes the effects of BK on the ultrastructure and proteome of the rat retina. The effects of intravitreal injection of BK on retinal thickness and vascular ultrastructure in Sprague Dawley rats were analyzed and compared with the effects of VEGF using spectral-domain optical coherence tomography. At 24 h post intravitreal injection of BK or saline vehicle retina were harvested and solubilized proteins were analyzed by mass spectrometry-based proteomics. Proteins were identified using X!Tandem and spectral counts were used as a semiquantitative measurement of protein abundance. Proteins identified from retinal extracts were annotated by Gene Ontology (GO) slim terms and compared with a human DME vitreous proteome. Intravitreal injection of BK and VEGF induced transient increases in retinal thickness of 46 μm (24.6%, p = 0.015) and 39 μm (20.3%, p = 0.004), respectively at 24 h, which were resolved to baseline thicknesses at 96 h post injection. BK and VEGF also increased retinal vessel diameters and tortuosity at 24 h post intravitreal injection. Proteomic analyses identified 1757 non-redundant proteins in the rat retina, including 1739 and 1725 proteins from BK- and saline control-injected eyes, respectively. Eighteen proteins, including two proteins associated with intercellular junctions, filamin A and actinin alpha 4, were decreased by at least 50% (p < 0.05) in retina from BK-injected eyes compare with retina from eyes injected with saline. In addition, 32 proteins were increased by > 2-fold (p < 0.05) in retina from BK-injected eyes. Eight proteins, including complement C3, were identified to be increased in both BK-stimulated rat retina and in human DME vitreous. Western blot analysis showed that Complement 3 levels in vitreous from BK-injected eyes in rats and clinical DME samples were increased by 6.6-fold (p = 0.039) and 4.3-fold (p = 0.02), compared with their respective controls. In summary, this study identifies protein changes in rat retina that are associated with BK-induced retinal thickening, including 8 proteins that were previously reported to be increased in the human DME vitreous proteome.

Authors+Show Affiliations

Joslin Diabetes Center, Boston, MA, USA; KalVista Pharmaceuticals Inc, Cambridge, MA, USA.Joslin Diabetes Center, Boston, MA, USA; Beetham Eye Institute. Joslin Diabetes Center, Boston, MA, USA.Joslin Diabetes Center, Boston, MA, USA; Beetham Eye Institute. Joslin Diabetes Center, Boston, MA, USA.Chinese Academy of Sciences, Beijing, China.Joslin Diabetes Center, Boston, MA, USA; KalVista Pharmaceuticals Inc, Cambridge, MA, USA. Electronic address: epf@kalvista.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31351056

Citation

Murugesan, Nivetha, et al. "Retinal Proteome Associated With Bradykinin-induced Edema." Experimental Eye Research, vol. 186, 2019, p. 107744.
Murugesan N, Fickweiler W, Clermont AC, et al. Retinal proteome associated with bradykinin-induced edema. Exp Eye Res. 2019;186:107744.
Murugesan, N., Fickweiler, W., Clermont, A. C., Zhou, Q., & Feener, E. P. (2019). Retinal proteome associated with bradykinin-induced edema. Experimental Eye Research, 186, p. 107744. doi:10.1016/j.exer.2019.107744.
Murugesan N, et al. Retinal Proteome Associated With Bradykinin-induced Edema. Exp Eye Res. 2019;186:107744. PubMed PMID: 31351056.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Retinal proteome associated with bradykinin-induced edema. AU - Murugesan,Nivetha, AU - Fickweiler,Ward, AU - Clermont,Allen C, AU - Zhou,Qunfang, AU - Feener,Edward P, Y1 - 2019/07/24/ PY - 2018/12/03/received PY - 2019/06/19/revised PY - 2019/07/22/accepted PY - 2019/7/28/pubmed PY - 2019/7/28/medline PY - 2019/7/28/entrez KW - Bradykinin KW - Diabetic macular edema KW - Plasma-kallikrein kinin system KW - Retinal proteomics SP - 107744 EP - 107744 JF - Experimental eye research JO - Exp. Eye Res. VL - 186 N2 - The plasma kallikrein-stimulated generation of bradykinin (BK) has been implicated in diabetic macular edema (DME). This study characterizes the effects of BK on the ultrastructure and proteome of the rat retina. The effects of intravitreal injection of BK on retinal thickness and vascular ultrastructure in Sprague Dawley rats were analyzed and compared with the effects of VEGF using spectral-domain optical coherence tomography. At 24 h post intravitreal injection of BK or saline vehicle retina were harvested and solubilized proteins were analyzed by mass spectrometry-based proteomics. Proteins were identified using X!Tandem and spectral counts were used as a semiquantitative measurement of protein abundance. Proteins identified from retinal extracts were annotated by Gene Ontology (GO) slim terms and compared with a human DME vitreous proteome. Intravitreal injection of BK and VEGF induced transient increases in retinal thickness of 46 μm (24.6%, p = 0.015) and 39 μm (20.3%, p = 0.004), respectively at 24 h, which were resolved to baseline thicknesses at 96 h post injection. BK and VEGF also increased retinal vessel diameters and tortuosity at 24 h post intravitreal injection. Proteomic analyses identified 1757 non-redundant proteins in the rat retina, including 1739 and 1725 proteins from BK- and saline control-injected eyes, respectively. Eighteen proteins, including two proteins associated with intercellular junctions, filamin A and actinin alpha 4, were decreased by at least 50% (p < 0.05) in retina from BK-injected eyes compare with retina from eyes injected with saline. In addition, 32 proteins were increased by > 2-fold (p < 0.05) in retina from BK-injected eyes. Eight proteins, including complement C3, were identified to be increased in both BK-stimulated rat retina and in human DME vitreous. Western blot analysis showed that Complement 3 levels in vitreous from BK-injected eyes in rats and clinical DME samples were increased by 6.6-fold (p = 0.039) and 4.3-fold (p = 0.02), compared with their respective controls. In summary, this study identifies protein changes in rat retina that are associated with BK-induced retinal thickening, including 8 proteins that were previously reported to be increased in the human DME vitreous proteome. SN - 1096-0007 UR - https://www.unboundmedicine.com/medline/citation/31351056/Retinal_proteome_associated_with_bradykinin-induced_edema L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-4835(18)30880-7 DB - PRIME DP - Unbound Medicine ER -