TY - JOUR
T1 - Trabecular meshwork bradykinin receptors
T2 - MRNA levels, immunohistochemical visualization, signaling processes pharmacology, and linkage to IOP reduction
AU - Sharif, Najam A.
AU - Katoli, Parvaneh
AU - Kelly, Curtis R.
AU - Li, Linya
AU - Xu, Shouxi
AU - Wang, Yu
AU - Klekar, Laura
AU - Earnest, David
AU - Yacoub, Shenouda
AU - Hamilton, Gwenette
AU - Jacobson, Nasreen
AU - Shepard, Allan R.
AU - Ellis, Dorette Zoe
PY - 2014/2/1
Y1 - 2014/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84892926058&partnerID=8YFLogxK
U2 - 10.1089/jop.2013.0105
DO - 10.1089/jop.2013.0105
M3 - Article
C2 - 24236827
AN - SCOPUS:84892926058
SN - 1080-7683
VL - 30
SP - 21
EP - 34
JO - Journal of Ocular Pharmacology and Therapeutics
JF - Journal of Ocular Pharmacology and Therapeutics
IS - 1
ER -