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Jaeyoung Heo, Emily Ahadizadeh, Yuxi Zheng, Min Hyung Kang, Douglas J Rhee; Adenoviral Gene Transfer of TGF-β2 Upregulates Intraocular Pressure through SPARC and Integrin-Linked Kinase in Mice. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5156.
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Intraocular pressure (IOP) is a modifiable risk factor for primary open-angle glaucoma (POAG).  Transforming growth factor-beta-2 (TGF-β2) and Secreted Protein, Acidic, and Rich in Cysteine (SPARC) have been known to play a regulatory role for IOP by changing extracellular matrix (ECM) composition in the eye. [2,3] TGF-β2 has been shown to upregulate SPARC and ECM proteins such as collagens and fibronectin, which then elevates IOP in the human trabecular meshwork (TM) and rodents. [4,5] Integrin-linked kinase (ILK) is a widely expressed serine/threonine kinase that regulates ECM organization through signaling cascades by interacting with SPARC.  We hypothesize that TGF-β2 upregulates intraocular pressure through SPARC and ILK in mice.
Mice were injected with adenovirus carrying cDNA of TGF-β2 (Ad-TGF-β2) and a Lentivirus carrying short-hairpin RNA targeting human ILK (Lenti-shILK). The Ad5 vector system was used to construct the adenovirus (Ad- TGF β2) and the pLKO.1 vector system was used to construct the Lentivirus (Lenti-shILK).Ad-TGF-β2 was used to upregulate SPARC in the mice at the multiplicity of infection (MOI) 50, and Lenti-shILK was used to inhibit ILK at MOI 10. The mice were assessed for changes in intraocular pressure (IOP) using the rebound tonometer and at peak IOP, immunohistochemistry was preformed.
There was a significant difference (P<0.05) in IOPs between the eyes injected withAd. TGF-β2+shControl and Ad. TGF-β2+Lenti-shILK injected eyes on day seven and ten. In addition, there was also a significant difference (P<0.05) in IOPs between the eyes injected with the Ad. TGF-β2+shControl and uninjected contralateral eyes (No treatment) on day 7 and 10 as well.
The effect of TGF-β2 mediated ocular hypertension is through the SPARC/ILK signaling pathway.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
Figure: IOP measurement of IOP in the eyes of mice who have TGF-2 overexpressed and were treated with either Lenti-shControl (“shControl”) or Lenti-shILK (“shILK”). The contralateral eye in the two treatment groups served as uninjected controls (“No Treatment”). When compared to the IOPs of No Treatment, the IOP increase of Ad. TGF-2 +shControl injected WT mice is significant during days 7-10. In addition, compared to the IOPs of Ad.SPARC+shILK, the IOP increase of Ad.SPARC+shControl is significantly higher on days 7-10. Data are presented as mean ± SEM. *P<0.05, #P<0.05
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