Tight Junction Claudins and the Kidney in Sickness and in Health
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View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1788 (2009) 858–863 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbamem Review Tight junction claudins and the kidney in sickness and in health Daniel F. Balkovetz ⁎ Veterans Administration Medical Center, University of Alabama at Birmingham, Birmingham, AL 35294-0007, USA Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294-0007, USA Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294-0007, USA Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL 35294-0007, USA article info abstract Article history: The epithelial cell tight junction has several functions including the control of paracellular transport between Received 24 March 2008 epithelial cells. Renal paracellular transport has been long recognized to exhibit unique characteristics within Received in revised form 24 June 2008 different segments of the nephron, functions as an important component of normal renal physiology and has Accepted 8 July 2008 been speculated to contribute to renal related pathology if functioning abnormally. The discovery of a large Available online 16 July 2008 family of tight junction associated 4-transmembrane spanning domain proteins named claudins has advanced our understanding on how the paracellular permeability properties of tight junctions are Keywords: fi Metabolic acidosis determined. In the kidney, claudins are expressed in a nephron-speci c pattern and are major determinants Acute kidney injury of the paracellular permeability of tight junctions in different nephron segments. The combination of Tight junction nephron segment claudin expression patterns, inherited renal diseases, and renal epithelial cell culture Zonula occludens models is providing important clues about how tight junction claudin molecules function in different Familial hypomagnesemia with hypercalciuria segments of the nephron under normal and pathological conditions. This review discusses early observations and nephrocalcinosis of renal tubule paracellular transport and more recent information on the discovery of the claudin family of Hepatocyte growth factor tight junction associated membrane proteins and how they relate to normal renal function as well as diseases Hepatitis C of the human kidney. Membranoproliferative glomeronephritis WNK Published by Elsevier B.V. Hypertension Claudin Contents 1. Introduction .............................................................. 858 2. Early observations of renal paracellular transport ............................................. 859 3. Discovery of claudins .......................................................... 859 4. Molecular mechanism of tight junction charge selectivity by claudins ................................... 860 5. Distribution of claudin isoforms in the kidney .............................................. 860 6. Role of claudins in renal related disease conditions ............................................ 861 6.1. Familial hypomagnesemia with hypercalcuria and nephrocalcinosis a human disease of the tight junction proteins claudin-16 and claudin-19 .......................................................... 861 6.2. Claudins and the WNK (with no K (lysine) protein kinase) family of protein kinases — a genetic form of human hypertension ..... 861 6.3. Altered claudin expression in acute kidney injury ......................................... 862 6.4. Potential roles of claudins in potassium and acid/base homeostasis ................................. 862 7. Conclusions .............................................................. 862 Acknowledgements ............................................................. 862 References. ................................................................. 862 ⁎ Department of Medicine, 1530 3rd Avenue South, LHRB 642, University of Alabama at Birmingham, Birmingham, AL 35294-0007, USA. Tel.: +1 205 934 3589; fax: +1 205 975 6288. E-mail address: [email protected]. 0005-2736/$ – see front matter. Published by Elsevier B.V. doi:10.1016/j.bbamem.2008.07.004 D.F. Balkovetz / Biochimica et Biophysica Acta 1788 (2009) 858–863 859 1. Introduction 2. Early observations of renal paracellular transport The tight junction, originally described as the zonula occludens [1], The reabsorption and secretion of various solutes across the renal is one of the three epithelial cell junctional complexes that are tubular epithelium represents a fundamental aspect of renal physiol- important for the development and maintenance of epithelial cell ogy. Transported solutes cross the renal tubular epithelium by either polarity and an intact barrier in all epithelial organs. These junctional the transcellular or paracellular route [12]. In the transcellular route, complexes also include anchoring junctions and communicating the solutes cross the apical membrane, traverse through the junctions. The anchoring junctions are subdivided into actin filament cytoplasm, and then exit the cell across the basolateral membrane. associated complexes and intermediate filament associated com- The transcellular pathway may also occur in the basolateral to apical plexes. The actin filament based anchoring junctions include focal direction as seen in the case of immunoglobulin transcytosis by the adhesions (mediated in part by integrin molecules) that attach the polymeric immunoglobulin receptor [13]. Specific membrane trans- cells to the extracellular matrix and the adherens junction (mediated port proteins on the apical and/or basolateral membrane frequently in part by the transmembrane protein E-cadherin and cytosolic facilitate this process. In the case of transepithelial transport by the proteins called catenins) that is localized to the lateral membranes of paracellular route, solutes cross by going through the epithelial tight adjacent cells. The intermediate filament associated anchoring junction between adjacent epithelial cells. Much less is understood junctions include desmosomes (mediated in part by cadherin about the mechanisms of paracellular transport compared to what is molecules) that are also localized to the lateral membranes of known about transcellular transport processes. adjacent epithelial cells and hemidesmosomes (mediated in part by Approximately 40years ago, the identification of renal paracellular integrin molecules) that also attach the cells to the extracellular transport processes originated from work by renal physiologists matrix. The communicating junctions consist of gap junctions measuring renal proximal tubule transepithelial potentials with (mediated by connexins) that are important for cell–cell communica- microelectrodes [14]. The results from these measurements showed tion. The tight junction (also referred to as the occluding junction) is both that the proximal tubular epithelium is an extremely leaky located at the most apical region of the lateral membrane in epithelial structure (the overall resistance is only 5–12Ω cm2 [15–18] and varies cell sheets. Tight junctions are composed of transmembrane and with the distance from the glomerulus), and that most of the high cytosolic proteins and seal the intercellular space between adjacent conductance is due to sodium ions rather than chloride ions [19]. The cells to create a primary barrier against the diffusion of fluid, microelectrode studies allowed for recognition and quantification of electrolytes, macromolecules and pathogens via the paracellular proximal tubule leakiness and determined the transport mechanism pathway [2–4]. Two major functions of the epithelial tight junction to occur via the paracellular route through the tight junction. This are simply characterized as the gate and fence functions [5]. The tight paracellular pathway was also referred to as a shunt by investigators. junction gate function refers to the control of movement of molecules Early quantification of the proximal tubule shunt pathway was between epithelial cells via the paracellular route. The tight junction is achieved by analyzing the glucose-induced potential changes in rat essential for the barrier function of epithelia by restricting paracellular proximal tubules, and the results indicated that the shunt conduc- diffusion. Tight junctions encircle the epithelial cells at the apical end tance was ∼ 70 times higher than the conductance of the cellular of the lateral membrane and form the boundary between the apical transport pathway [20]. This observation suggested that virtually all and basolateral membrane surfaces. The tight junction fence function passive uncoupled ion flow passes through the shunt (paracellular refers to the maintenance of epithelial cell polarity. Tight junctions are pathway), while all active transport proceeds through the cell crucial for the development and maintenance of epithelial cell surface membranes (transcellular pathway). polarity, since they form an intra-membrane diffusion fence that Early investigation of tight junction permeability in the cortical restricts diffusion of lipids in the exoplasmic leaflet of the plasma collecting duct was investigated using lanthanum tracer techniques membrane [6,7]. Expression of a mutated tight junction associated [21]. These studies demonstrated that the tight junctions of the membrane protein (occludin, see below) was found to render proximal and