Sharif, Naj, Katoli, Parvaneh, Kelly, Curtis, Li, Linya, Xu, Shouxi, Wang, Yu, Klekar, Laura, Earnest, David, Yacoub, Shenouda, Hamilton, Gwen, Jacobson, Nasreen, 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