June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Angiotensin II type 1 receptor blockers lower IOP in mice and reduce TGFβ signaling in retinal ganglion cells
Author Affiliations & Notes
  • Ralph J Hazlewood
    Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • John Kuchtey
    Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Rachel W Kuchtey
    Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Footnotes
    Commercial Relationships   Ralph Hazlewood, None; John Kuchtey, None; Rachel Kuchtey, None
  • Footnotes
    Support  NIH Grant EY020894 & EY008126, Marfan Foundation
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 4917. doi:
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    • Get Citation

      Ralph J Hazlewood, John Kuchtey, Rachel W Kuchtey; Angiotensin II type 1 receptor blockers lower IOP in mice and reduce TGFβ signaling in retinal ganglion cells. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4917.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Angiotensin II type 1 receptor blockers (ARBs) are commonly used to treat systemic hypertension. In addition to interfering with the renin-angiotensin system (RAS), ARBs attenuate signaling via TGFβ. ARBs also exhibit neuroprotective effects in glaucoma models, but their ability to lower IOP is debated. Currently, there are eight ARBs in clinical use in the US, each with different chemical structures, active metabolites, and different modes of binding to angiotensin II type 1 receptor (AT1R). The purpose of this study is to investigate the IOP lowering capability of ARBs as potential treatments for glaucoma.

Methods : The ARBs losartan, irbesartan, telmisartan, or vehicle controls were administered orally to 3 month-old C57BL/6 mice for 7 days. Before and after treatment, IOP was measured by TonoLab rebound tonometry and blood pressure (BP) was measured by tail-cuff method. Following measurements, mice were sacrificed and eyes were enucleated and processed for immunohistochemistry (IHC) for components of the RAS pathway.

Results : BP was significantly reduced in all ARB treatment groups. Expression of AT1R, renin, and phosphorylated SMAD2 (a marker of TGFβ signaling) was altered in the retina following ARB treatment. IOP was not affected by losartan administration after 3 days and 7 days. However, IOP was significantly reduced after 3 days and 7 days of treatment with irbesartan (p < 0.001, n = 14 and p < 10-4, n = 8, respectively) as well as after treatment with telmisartan (3 days p < 10-4, n = 12 and 7 days p < 0.05, n = 8).

Conclusions : Oral administration of ARBs results in physiologically relevant drug concentrations, as evidenced by lower systemic BP and changes in RAS component expression in the eye after treatment with all ARBs tested. ARB administration lowers TGFβ signaling in the eye, as has been shown for other tissues. IOP-lowering capability varies by specific ARB used, with losartan having no effect, in agreement with previous results. On the other hand, telmisartan and irbesartan administration results in significant lowering of IOP. Considering that TGFβ is elevated in glaucoma subjects, combined with inhibitory effects on TGFβ signaling, ARBs with IOP-reducing capabilities may be novel treatments for glaucoma.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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