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Fig. 3. PKC isozymes in the blood-retinal barrier. In endothelial cells, both classical and atypical PKC isozymes contribute to VEGF signaling. VEGF activates classical PKCs, such as PKCb (beta) leading to phosphorylation of the tight junction protein occludin and promoting internalization and subsequent endothelial permeability. Ruboxistaurin inhibition of PKCb (beta) prevents VEGF-induced permeability by blocking this pathway. Concurrently, atypical PKC isoforms, such as PKCz (zeta), lead to increased endothelial permeability via unknown mechanisms. However, inhibition of atypical PKC activity effectively blocks both growth factor and inflammatory-cytokine- induced endothelial permeability. In pericytes, hyperglycemia-induced increase of novel PKCs, specifically PKCd (delta), inhibits PDGFb (beta) survival signaling to Akt, leading to pericyte apoptosis. Loss of pericytes, coupled with VEGF-induced endothelial permeability likely contributes to the macular edema observed in diabetic retinopathy.
CONCLUSIONS
Vascular permeability in diabetic retinopathy may be attributed to a host of changes in the retina, including increases in growth factors such as VEGF, cytokines like TNFa (alpha), or protease activation such as kallikrein/bradykinin system. Posttranslational modification of the junction proteins and regulated endocytosis is an important mechanism controlling retinal vascular permeability. Indeed, VEGF activation of PKCb (beta) controls occludin phosphorylation and subsequent ubiquitination necessary for VEGF-induced permeability. As information regarding changes to the junction complex becomes better understood, more targeted therapies may become available, increasing our ability to maintain retinal vascular integrity and visual function in the face of diabetes.
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