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Trabecular meshwork bradykinin receptors: mRNA levels, immunohistochemical visualization, signaling processes pharmacology and linkage to IOP changes

Sharif, Naj and Katoli, Parvaneh and Kelly, Curtis and Li, Linya and Xu, Shouxi and Wang, Yu and Klekar, Laura and Earnest, David and Yacoub, Shenouda and Hamilton, Gwen and Jacobson, Nasreen and Shepard, Allan and Ellis, Dorette (2014) Trabecular meshwork bradykinin receptors: mRNA levels, immunohistochemical visualization, signaling processes pharmacology and linkage to IOP changes. J Ocular Pharmacology & Therapeutics, 30 (1). pp. 21-34.

Abstract

Background: To localize mRNA and protein of bradykinin (BK) receptors, BK precursor polypeptide (kininogen) mRNA, and to study functional biochemical pharmacology of the signal transduction processes mediated by B2-receptors in isolated human trabecular meshwork (h-TM) cells. Intraocular pressure (IOP) lowering effects of two kinins were also investigated.
Methods: Previously documented procedures were utilized throughout these studies.
Results: Kinninogen mRNA was most abundant in TM, ciliary body (CB) and optic nerve head and appeared elevated in glaucomatous human TM tissue. High levels of B2-receptor mRNA were found in the sclera, iris, TM, and CB. B2-receptor subtype protein was localized in cells of the monkey and human TM, and treatment of isolated h-TM cells with transforming growth factor-β2 (5 ng/ ml) caused significant (p<0.04) down-regulation of B2-receptor mRNA. In isolated primary h-TM cells, BK (EC50 = 0.8 ± 0.2 nM; n = 19) and Met-Lys-BK (EC50 = 6.5 ± 1.5 nM) mobilized intracellular Ca2+ and induced release of prostaglandins (PGs) that was blocked by two B2-receptor antagonists (HOE-140; (S)-WIN-64338). The cyclooxygenase inhibitor bromfenac, abolished BK-induced PGs production. BK concentration-dependently increased cell impedance and it significantly (p < 0.05) decreased h-TM cell volume in vitro. Intravitreal (ivt) administration of BK (50 µg), but not a B1-agonist (Sar-[D-Phe9]-Des-Arg9-BK), efficaciously lowered Dutch-Belt rabbit IOP.
Conclusions: BK activates multiple signal transduction pathways in h-TM cells via B2-receptors that also mediate IOP reduction as observed in rabbits following ivt administration of BK. These ocular hypotensive effects of BK may be physiologically important.

Item Type: Article
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/9993

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