Attainment of polarity promotes growth factor secretion by retinal pigment epithelial cells: relevance to age-related macular degeneration.
The antiangiogenic and neurotrophic growth factor, pigment epithelial derived factor (PEDF), and the proangiogenic growth factor, vascular endothelial growth factor-A (VEGF), are released from retinal pigment epithelial (RPE) cells where they play a critical role in the pathogenesis of age-related macular degeneration (AMD). Since RPE polarity may be altered in advanced AMD, we studied the effect of polarization of differentiated, human RPE monolayer cultures on expression and secretion of PEDF and VEGF. Polarized RPE demonstrated apical microvilli, expression of tight junction proteins, apical localization of Na/K- ATPase, and high transepithelial resistance (490 +/- 17 Omega x cm(2)). PEDF secretion was about 1000 fold greater than that for VEGF in both polarized and non-polarized cultures. Polarization of the RPE monolayer increased PEDF secretion, which was predominantly apical, by 34 fold (p<0.02) and VEGF secretion, which was predominantly basolateral, by 5.7 fold (p<0.02). Treatment of non-polarized RPE cultures with bone morphogenetic protein-4 (BMP-4) had no effect on PEDF or VEGF secretion, but resulted in a dose-dependent >2-fold increase in basolateral VEGF secretion (p<0.05) in polarized cultures. Our data show that polarity is an important determinant of the level of PEDF and VEGF secretion in RPE and support the contention that loss of polarity of RPE in AMD results in marked loss of neurotrophic and vascular support for the retina potentially leading to photoreceptor loss and blindness.
Department of Ophthalmology, Keck School of Medicine of University of Southern California, Los Angeles, CA 90089, USA.
Shozo
S
Sonoda
Parameswaran G
PG
Sreekumar
Satoru
S
Kase
Christine
C
Spee
Stephen J
SJ
Ryan
Ram
R
Kannan
David R
DR
Hinton
D000375:Aging / Q000473:pathology* / Q000502:physiology; D002453:Cell Cycle; D016764:Cell Polarity / Q000502:physiology*; D049109:Cell Proliferation; D005136:Eye Proteins / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D008268:Macular Degeneration / Q000378:metabolism / Q000473:pathology*; D008854:Microscopy, Electron; D009414:Nerve Growth Factors / Q000378:metabolism*; D055213:Retinal Pigment Epithelium / Q000378:metabolism / Q000648:ultrastructure*; D015843:Serpins / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D000099174:Pigment Epithelium-Derived Factor
D005136:Eye Proteins; D009414:Nerve Growth Factors; D015843:Serpins; D042461:Vascular Endothelial Growth Factor A; D000099174:Pigment Epithelium-Derived Factor
BMP-4; PEDF; VEGF-A; age-related macular degeneration; cell polarity; retinal pigment epithelial cell