Review
Regulation of tight junctions and loss of barrier function in pathophysiology

https://doi.org/10.1016/j.biocel.2003.08.007Get rights and content

Abstract

The mechanism by which epithelial and endothelial cells interact to form polarized tissue is of fundamental importance to multicellular organisms. Dysregulation of these barriers occurs in a variety of diseases, destroying the normal cellular environments and leading to organ failure. Increased levels of growth factors are a common characteristic of diseases exhibiting tissue permeability, suggesting that growth factors play a direct role in elevating permeability. Of particular concern for this laboratory, increased expression of vascular endothelial growth factor may enhance vascular permeability in diabetic retinopathy, leading to vision impairment and blindness. However, the mechanism by which growth factors increase permeability is unclear. Polarized cells form strong barriers through the development of tight junctions, which are specialized regions of the junctional complex. Tight junctions are composed of three types of transmembrane proteins, a number of peripheral membrane structural proteins, and are associated with a variety of regulatory proteins. Recent data suggest that growth factor-stimulated alterations in tight junctions contribute to permeability in a variety of disease states. The goal of this review was to elucidate potential mechanisms by which elevated growth factors elicit deregulated paracellular permeability via altered regulation of tight junctions, with particular emphasis on the tight junction proteins occludin and ZO-1, protein kinase C signaling, and endocytosis of junctional proteins. Understanding the molecular mechanisms underlying growth factor-mediated regulation of tight junctions will facilitate the development of novel treatments for diseases such as brain tumors, diabetic retinopathy and other diseases with compromised tight junction barriers.

Introduction

The mechanism by which polarized epithelial and endothelial cells form a permeability barrier is a fundamental question in cell biology. Breakdown of a regulated barrier occurs in many diseases and affects both epithelial and endothelial cells. Examples of such diseases include ischemic retinopathies, pulmonary edema, inflammatory bowel disease, nephropathies, tumors, delayed hypersensitivity reactions, rheumatoid arthritis, and psoriasis. A common feature of these diseases is that increased tissue permeability is associated with elevated levels of one or more growth factors. For example, increased vascular endothelial growth factor (VEGF) in the eyes of patients with diabetes stimulates vascular permeability that proceeds to vision impairment and vision loss; however, the mechanisms by which VEGF increases endothelial permeability are not well understood. The overall goal of this review was to describe potential mechanisms by which elevated growth factors elicit unregulated paracellular permeability via altered regulation of tight junctions.

Section snippets

Components

Tight junctions, or zonula occludens, are the most apical component of the intercellular junctional complex, which also includes adherens junctions, desmosomes, and gap junctions. Tight junctions visualized by electron microscopy are regions where the outer leaflets of plasma membranes from adjacent cells appear to fuse together and obliterate the intercellular space and may extend in depth from 0.2 to 0.5 μm (Farquhar & Palade, 1963). The tight junctions form a barrier to diffusion of molecules

Protein kinase C family background

The protein kinase C (PKC) family consists of 11 members of serine/threonine kinases that are activated by diverse mechanisms including receptor tyrosine kinases, non-receptor tyrosine kinases, and G protein-coupled receptors (Newton, 1995). PKC isoforms are classified into three groups based on their structure and particular substrate requirements: conventional (α, βI, βII, γ), novel (δ, ε, η, θ, μ), and atypical (ζ, λ/ι) (Newton, 1995). Conventional PKC isoforms require diacylglycerol (DAG),

Endocytosis

Endocytosis is a regulated cellular process in which integral membrane proteins are internalized and directed to distinct cellular compartments. Endocytosis of integral membrane proteins may be mediated by clathrin-coated pits, caveolae, or other components of the plasma membrane. Discrete regions of the membrane invaginate and bud into the cytoplasm as vesicles in an energy-dependent process requiring dynamin GTPase (McNiven, Cao, Pitts, & Yoon, 2000; Henley, Krueger, Oswald, & McNiven, 1998).

Conclusions

Our central aim was to review potential mechanisms by which growth factors effect paracellular permeability by regulating tight junctions. Several signaling pathways have been identified that contribute to elevated permeability either by regulation of specific tight junction proteins or the cytoskeleton. Our laboratory is specifically interested in elucidating the mechanisms of vascular permeability in diabetic retinopathy. VEGF and other growth factors are elevated in diabetic retinopathy and

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