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

Najam A. Sharif, Parvaneh Katoli, Curtis R. Kelly, Linya Li, Shouxi Xu, Yu Wang, Laura Klekar, David Earnest, Shenouda Yacoub, Gwenette Hamilton, Nasreen Jacobson, Allan R. Shepard, Dorette Zoe Ellis

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4 Scopus citations

Abstract

Purpose: 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 B 2-receptors in isolated human trabecular meshwork (h-TM) cells. Intraocular pressure (IOP) lowering effects of 2 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 h-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 h-TM, and the treatment of isolated h-TM cells with transforming growth factor-β2 (5 ng/mL) caused significant (P<0.04) downregulation of B 2-receptor mRNA. In isolated primary h-TM cells, BK (EC 50=0.8±0.2 nM; n=19) and Met-Lys-BK (EC50=6. 5±1.5 nM) mobilized intracellular Ca2+ and induced the release of prostaglandins (PGs) that was blocked by 2 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 B 1-agonist (Sar-[D-Phe9]-Des-Arg9-BK; also at 50 μg), efficaciously lowered IOP (22.9% to 37% from baseline) of Dutch-Belted rabbits that naturally have high IOPs (27-28 mmHg). 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 and suggest a novel therapeutic potential of BK-related B2-agonists.

Original languageEnglish
Pages (from-to)21-34
Number of pages14
JournalJournal of Ocular Pharmacology and Therapeutics
Volume30
Issue number1
DOIs
StatePublished - 1 Feb 2014

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    Sharif, N. A., Katoli, P., Kelly, C. R., Li, L., Xu, S., Wang, Y., Klekar, L., Earnest, D., Yacoub, S., Hamilton, G., Jacobson, N., Shepard, A. R., & Ellis, D. Z. (2014). Trabecular meshwork bradykinin receptors: MRNA levels, immunohistochemical visualization, signaling processes pharmacology, and linkage to IOP reduction. Journal of Ocular Pharmacology and Therapeutics, 30(1), 21-34. https://doi.org/10.1089/jop.2013.0105