Advertisement

The influence of systemic renin-angiotensin-inhibition on ocular cytokines related to proliferative vitreoretinopathy

  • Robert Hoerster
  • Sascha Fauser
  • Claus Cursiefen
  • Bernd Kirchhof
  • Ludwig M. Heindl
Retinal Disorders

Abstract

Purpose

The renin-angiotensin system is involved in the pathogenesis of fibrosis in several organs via induction of transforming growth factor (TGF) beta. In the pathogenesis of proliferative vitreoretinopathy (PVR) TGF-beta plays a pivotal role, promoting transition of retinal pigment epithelial (RPE) cells into myofibroblasts. We studied the influence of angiotensin converting enzyme-inhibition (ACEI) on cytokines and growth factors, related to PVR in aqueous humor.

Methods

We performed a post hoc analysis of a prospectively conducted interventional case series. From patients with rhegmatogenous retinal detachment (RRD) aqueous humor was obtained during primary surgery and analyzed using multiplex bead analysis for interferon gamma, tumor necrosis factor alpha, CC-chemokine ligand (CCL) 2 / monocyte chemoattractant protein (MCP)-1, interleukin (IL)-1 beta, IL-2, IL-4, IL-6, IL-8, vascular endothelial growth factor (VEGF)-A, platelet derived growth factor (PDGF)-aa, TGF-beta 1, TGF-beta 2, TGF-beta 3, fibroblast growth factor (FGF)-aa, and FGF-bb. We recorded information about systemic ACEI from the medical history.

Results

In the primary study elevated levels of TGF-beta 1 and 2, IL 6 and 8 and CCL2/MCP-1 were a risk factor for later PVR development. Here, systemic ACEI neither influenced levels of these cytokines and growth factors, nor of any other tested in this study (p ≥ 0.438, respectively). Also the incidence of PVR development was unaffected (p = 0.201).

Conclusion

The systemic intake of ACEI for arterial hypertension does not influence levels of profibrotic cytokines/growth factors in aqueous humor. Further studies need to clarify if relevant levels of ACEI accumulate in the eye, and if direct administration of ACEI in experimental PVR could be beneficial.

Keywords

Proliferative vitreoretinopathy Treatment Angiotensin converting enzyme Renin Cytokines Growth factors 

Notes

Acknowledgements

RH received support within the Köln Fortune study program from the University of Cologne. None of the authors has any conflicts of interest to declare regarding the content of this study.

Compliance with ethical standards

Author statement

Funding

The University of Cologne provided financial support within the Köln Fortune study program in the form of funding personnel costs of RH and laboratory materials for the study. The sponsor had no role in the design or conduct of this research.

Conflict of interest

All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.

Ethical approval

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Glaser BM, Cardin A, Biscoe B (1987) Proliferative vitreoretinopathy. The mechanism of development of vitreoretinal traction. Ophthalmology 94:327–332CrossRefPubMedGoogle Scholar
  2. 2.
    Pastor JC (1998) Proliferative vitreoretinopathy: an overview. Surv Ophthalmol 43:3–18CrossRefPubMedGoogle Scholar
  3. 3.
    Bochaton-Piallat ML, Kapetanios AD, Donati G, Redard M, Gabbiani G, Pournaras CJ (2000) TGF-beta1, TGF-beta receptor II and ED-A fibronectin expression in myofibroblast of vitreoretinopathy. Invest Ophthalmol Vis Sci 41:2336–2342PubMedGoogle Scholar
  4. 4.
    Connor TB Jr, Roberts AB, Sporn MB, Danielpour D, Dart LL, Michels RG, de Bustros S, Enger C, Kato H, Lansing M et al (1989) Correlation of fibrosis and transforming growth factor-beta type 2 levels in the eye. J Clin Invest 83:1661–1666CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Gamulescu MA, Chen Y, He S, Spee C, Jin M, Ryan SJ, Hinton DR (2006) Transforming growth factor beta2-induced myofibroblastic differentiation of human retinal pigment epithelial cells: regulation by extracellular matrix proteins and hepatocyte growth factor. Exp Eye Res 83:212–222CrossRefPubMedGoogle Scholar
  6. 6.
    Hoerster R, Hermann MM, Rosentreter A, Muether PS, Kirchhof B, Fauser S (2013) Profibrotic cytokines in aqueous humour correlate with aqueous flare in patients with rhegmatogenous retinal detachment. Br J Ophthalmol 97:450–453CrossRefPubMedGoogle Scholar
  7. 7.
    Kita T, Hata Y, Arita R, Kawahara S, Miura M, Nakao S, Mochizuki Y, Enaida H, Goto Y, Shimokawa H, Hafezi-Moghadam A, Ishibashi T (2008) Role of TGF-beta in proliferative vitreoretinal diseases and ROCK as a therapeutic target. Proc Natl Acad Sci U S A 105:17504–17509CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Nassar K, Grisanti S, Tura A, Luke J, Luke M, Soliman M, Grisanti S (2014) A TGF-beta receptor 1 inhibitor for prevention of proliferative vitreoretinopathy. Exp Eye Res 123:72–86CrossRefPubMedGoogle Scholar
  9. 9.
    Hoerster R, Muether PS, Vierkotten S, Hermann MM, Kirchhof B, Fauser S (2014) Upregulation of TGF-ss1 in experimental proliferative vitreoretinopathy is accompanied by epithelial to mesenchymal transition. Graefes Arch Clin Exp Ophthalmol 252:11–16CrossRefPubMedGoogle Scholar
  10. 10.
    Lee H, O’Meara SJ, O’Brien C, Kane R (2007) The role of gremlin, a BMP antagonist, and epithelial-to-mesenchymal transition in proliferative vitreoretinopathy. Invest Ophthalmol Vis Sci 48:4291–4299CrossRefPubMedGoogle Scholar
  11. 11.
    Nassar K, Luke J, Luke M, Kamal M, Abd El-Nabi E, Soliman M, Rohrbach M, Grisanti S (2011) The novel use of decorin in prevention of the development of proliferative vitreoretinopathy (PVR). Graefes Arch Clin Exp Ophthalmol 249:1649–1660CrossRefPubMedGoogle Scholar
  12. 12.
    Hatanaka H, Koizumi N, Okumura N, Kay EP, Mizuhara E, Hamuro J, Kinoshita S (2012) Epithelial-mesenchymal transition-like phenotypic changes of retinal pigment epithelium induced by TGF-beta are prevented by PPAR-gamma agonists. Invest Ophthalmol Vis Sci 53:6955–6963CrossRefPubMedGoogle Scholar
  13. 13.
    Parapuram SK, Chang B, Li L, Hartung RA, Chalam KV, Nair-Menon JU, Hunt DM, Hunt RC (2009) Differential effects of TGFbeta and vitreous on the transformation of retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 50:5965–5974CrossRefPubMedGoogle Scholar
  14. 14.
    Miyajima A, Chen J, Lawrence C, Ledbetter S, Soslow RA, Stern J, Jha S, Pigato J, Lemer ML, Poppas DP, Vaughan ED, Felsen D (2000) Antibody to transforming growth factor-beta ameliorates tubular apoptosis in unilateral ureteral obstruction. Kidney Int 58:2301–2313CrossRefPubMedGoogle Scholar
  15. 15.
    El Chaar M, Chen J, Seshan SV, Jha S, Richardson I, Ledbetter SR, Vaughan ED Jr, Poppas DP, Felsen D (2007) Effect of combination therapy with enalapril and the TGF-beta antagonist 1D11 in unilateral ureteral obstruction. Am J Physiol Renal Physiol 292:F1291–F1301CrossRefPubMedGoogle Scholar
  16. 16.
    Sun N, Zhai L, Li H, Shi LH, Yao Z, Zhang B (2016) Angiotensin-converting enzyme inhibitor (ACEI)-mediated amelioration in renal fibrosis involves suppression of mast cell degranulation. Kidney Blood Press Res 41:108–118CrossRefPubMedGoogle Scholar
  17. 17.
    Schroder S, Muether PS, Caramoy A, Hahn M, Abdel-Salam M, Diestelhorst M, Kirchhof B, Fauser S (2012) Anterior chamber aqueous flare is a strong predictor for proliferative vitreoretinopathy in patients with rhegmatogenous retinal detachment. Retina 32:38–42CrossRefPubMedGoogle Scholar
  18. 18.
    Ramirez M, Davidson EA, Luttenauer L, Elena PP, Cumin F, Mathis GA, De Gasparo M (1996) The renin-angiotensin system in the rabbit eye. J Ocul Pharmacol Ther 12:299–312CrossRefPubMedGoogle Scholar
  19. 19.
    Wolf G, Zahner G, Schroeder R, Stahl RA (1996) Transforming growth factor beta mediates the angiotensin-II-induced stimulation of collagen type IV synthesis in cultured murine proximal tubular cells. Nephrol Dial Transplant 11:263–269CrossRefPubMedGoogle Scholar
  20. 20.
    Gomez-Garre D, Ruiz-Ortega M, Ortego M, Largo R, Lopez-Armada MJ, Plaza JJ, Gonzalez E, Egido J (1996) Effects and interactions of endothelin-1 and angiotensin II on matrix protein expression and synthesis and mesangial cell growth. Hypertension 27:885–892CrossRefPubMedGoogle Scholar
  21. 21.
    Heindl LM, Schlotzer-Schrehardt U, Cursiefen C, Bachmann BO, Hofmann-Rummelt C, Kruse FE (2011) Myofibroblast metaplasia after descemet membrane endothelial keratoplasty. Am J Ophthalmol 151:1019–1023 e1012CrossRefPubMedGoogle Scholar
  22. 22.
    Matthaei M, Gillessen J, Muether PS, Hoerster R, Bachmann BO, Hueber A, Cursiefen C, Heindl LM (2015) Epithelial-mesenchymal transition (EMT)-related cytokines in the aqueous humor of Phakic and Pseudophakic Fuchs’ dystrophy eyes. Invest Ophthalmol Vis Sci 56:2749–2754CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.Department of OphthalmologyUniversity of CologneCologneGermany

Personalised recommendations