Diabetic retinopathy is a leading cause of vision loss in developed countries. Progression to sight threatening stages of diabetic retinopathy, including diabetic macular edema (DME), is usually associated with worsening of underlying retinal vascular dysfunction and disease, including an increase in the number and severity of retinal hemorrhages. Recent clinical advances have demonstrated that intravitreal injection of anti-VEGF directed therapies are effective in improving visual acuity and resolving macular edema in DME, and the FDA has recently approved intravitreal injection of ranibizumab for DME. While this treatment is highly effective for many patients with DME, several large clinical studies have revealed that about 40 to 50% of study subjects appear refractive or do not fully respond in the improvement of visual acuity and the resolution of retinal thickening to anti-VEGF directed therapies. These clinical findings suggest that VEGF-independent mechanisms might also contribute to retinal edema in a large number of DME patients. In recent reports and additional preliminary data, we show that plasma kallikrein (Pkal), factor FXII, and kininogen are increased in the vitreous of patients with DME. We also show that Pkal levels in the vitreous do not correlate with VEGF levels, revealing a component of molecular heterogeneity among DME patients. Using both knockout and pharmacological approaches, we show that Pkal contributes to retinal vascular hyperpermeability and retinal thickening in rodents and we have begun to characterize both bradykinin-dependent and -independent mechanisms that contribute to this response. Our studies have revealed that diabetes increases the effects of Pkal on vascular dysfunction and retinal edema (Clermont et al Diabetes 2011, Liu et al Nature Medicine 2011). We have also recently shown that autologous blood introduced into the vitreous increases retinal inflammation and retinal vascular permeability (Liu et al IOVS 2013) and the kallikrein system is as potent as VEGF in inducing retinal thickening. In addition we have used proteomics to characterize bradykinin-induced retinal edema and have identified a set of plasma proteins that are robustly increased in retinal edema coupled with striking decreases in a subset of retinal intermediate filament proteins. This grant will identify the PK- induced mechanisms that cause retinal vascular hyperpermeability and retinal thickening, and examine the hypothesis that the Pkal-bradykinin system is a VEGF-independent mediator of retinal dysfunction that contributes to DME.
The specific aims are 1) to characterize and compare the bradykinin receptor-dependent and independent effects of Pkal on retinal edema in diabetic mice, 2) to compare Pkal and VEGF-induced retinal edema and investigate interactions between these pathways, and 3) characterize the roles of nitric oxide synthase and calpain-mediated intermediate filament degradation/remodeling in retina edema. Further identification of the mechanism of action and regulation of the plasma kallikrein system in the retina will be helpful in evaluating potential clinical opportunities for targeting the Pkal system for the treatment of DME.
Diabetes macular edema is a leading cause of vision loss. Recent studies have revealed that an enzyme named plasma kallikrein in increased in the vitreous of people with diabetic retinopathy and contributes impairment to retinal vascular dysfunction via a pathway that is VEGF independent. This grant will perform studies using both knockout animal models and pharmacological approaches to identify the mechanisms of plasma kallikrein's effects on the retina and potential crosstalk with the VEGF pathway.
|Fein, Jordana G; Branchini, Lauren A; Manjunath, Varsha et al. (2014) Analysis of short-term change in subfoveal choroidal thickness in eyes with age-related macular degeneration using optical coherence tomography. Ophthalmic Surg Lasers Imaging Retina 45:32-7|
|Liu, Jia; Clermont, Allen C; Gao, Ben-Bo et al. (2013) Intraocular hemorrhage causes retinal vascular dysfunction via plasma kallikrein. Invest Ophthalmol Vis Sci 54:1086-94|
|Branchini, Lauren; Regatieri, Caio; Adhi, Mehreen et al. (2013) Effect of intravitreous anti-vascular endothelial growth factor therapy on choroidal thickness in neovascular age-related macular degeneration using spectral-domain optical coherence tomography. JAMA Ophthalmol 131:693-4|
|Liu, Jia; Feener, Edward P (2013) Plasma kallikrein-kinin system and diabetic retinopathy. Biol Chem 394:319-28|
|Choi, WooJhon; Potsaid, Benjamin; Jayaraman, Vijaysekhar et al. (2013) Phase-sensitive swept-source optical coherence tomography imaging of the human retina with a vertical cavity surface-emitting laser light source. Opt Lett 38:338-40|
|Grulkowski, Ireneusz; Liu, Jonathan J; Potsaid, Benjamin et al. (2013) High-precision, high-accuracy ultralong-range swept-source optical coherence tomography using vertical cavity surface emitting laser light source. Opt Lett 38:673-5|
|Feener, E P; Zhou, Q; Fickweiler, W (2013) Role of plasma kallikrein in diabetes and metabolism. Thromb Haemost 110:434-41|
|Branchini, Lauren; Regatieri, Caio V; Flores-Moreno, Ignacio et al. (2012) Reproducibility of choroidal thickness measurements across three spectral domain optical coherence tomography systems. Ophthalmology 119:119-23|
|Regatieri, Caio V; Branchini, Lauren; Fujimoto, James G et al. (2012) Choroidal imaging using spectral-domain optical coherence tomography. Retina 32:865-76|
|Baumann, Bernhard; Choi, WooJhon; Potsaid, Benjamin et al. (2012) Swept source/Fourier domain polarization sensitive optical coherence tomography with a passive polarization delay unit. Opt Express 20:10229-41|
Showing the most recent 10 out of 18 publications