ABSTRACT
The exact sites and molecules that determine resistance to aqueous humor drainage and control intraocular pressure (IOP) need further elaboration. Proposed sites include the inner wall of Schlemms's canal and the juxtacanalicular trabecular meshwork ocular drainage tissues. The adherens junctions (AJs) of Schlemm's canal endothelial cells (SECs) must both preserve the blood-aqueous humor (AQH) barrier and be conducive to AQH drainage. How homeostatic control of AJ permeability in SC occurs and how such control impacts IOP is unclear. We hypothesized that mechano-responsive phosphorylation of the junctional molecule VE-CADHERIN (VEC) by SRC family kinases (SFKs) regulates the permeability of SEC AJs. We tested this by clamping IOP at either 16 mmHg, 25 mmHg, or 45 mmHg in mice and then measuring AJ permeability and VEC phosphorylation. We found that with increasing IOP: 1) SEC AJ permeability increased, 2) VEC phosphorylation was increased at tyrosine-658, and 3) SFKs were activated at the AJ. Among the two SFKs known to phosphorylate VEC, FYN, but not SRC, localizes to the SC. Furthermore, FYN mutant mice had decreased phosphorylation of VEC at SEC AJs, dysregulated IOP, and reduced AQH outflow. Together, our data demonstrate that increased IOP activates FYN in the inner wall of SC, leading to increased phosphorylation of AJ VEC and, thus, decreased resistance to AQH outflow. These findings support a crucial role of mechanotransduction signaling in IOP homeostasis within SC in response to IOP. These data strongly suggest that the inner wall of SC partially contributes to outflow resistance.
ABSTRACT
BACKGROUND: Belatacept is a novel immunosuppressive therapy designed to improve clinical outcomes associated with kidney transplant recipients while minimizing use of calcineurin inhibitors (CNIs). METHODS: We searched for clinical trials related to administration of belatacept to kidney transplant patients compared to various immunosuppression regimens, as well as for studies that utilized data from belatacept trials to validate new surrogate measures. The purpose of this review is to consolidate the published evidence of belatacept's effectiveness and safety in renal transplant recipients to better elucidate its place in clinical practice. RESULTS: Analysis of the results from the Belatacept Evaluation of Nephroprotection and Effi-cacy as First-Line Immunosuppressive Trial (BENEFIT) study, a de novo trial that compared cyclosporine (CsA)-based therapy to belatacept-based therapy in standard criteria donors, found a significant difference in mean estimated glomerular filtration rate (eGFR) of 13-15 mL/min/1.73 m(2) and 23-27 mL/min/1.73 m(2) at 1 year and 7 years, respectively. The BENEFIT-EXT study was similarly designed with the exception that it included extended criteria donors. Renal function improved significantly for the more intensive belatacept group in all years of the BENEFIT-EXT study; however, it was not significant in the less intensive group until 5 years after transplant. Belatacept regimens resulted in lower blood pressure, cholesterol levels, and incidence of new-onset diabetes after transplant compared to CsA-based regimens. Results from conversion of CNIs to belatacept therapy, dual therapy of belatacept with sirolimus, and belatacept with corticosteroid avoidance therapy are also included in this article. CONCLUSION: The evidence reviewed in this article suggests that belatacept is an effective alternative in kidney transplant recipients. Compared to CNI-based therapy, belatacept-based therapy results in superior renal function and similar rates of allograft survival. In terms of safety, belatacept was shown to have lower incidence of hypertension, hyperlipidemia, and diabetes; however, incidence of posttransplantation lymphoproliferative disorder and the cost of belatacept may hinder use of this medication.
