Opening Pandora's box in the tight junction.

he epithelial tight junction (TJ) is one of the epithelial cell-cell junctional complexes and is critical for the maintenance of epithelial cell polarity and control of paracellular transport across epithelial tissues. In many renal physiology and nephrology textbooks, the renal epithelial TJ is simplistically depicted in cartoons as a box between epithelial cells with an arrow going through to illustrate the role of the TJ in paracellular transport (Figure 1). The understanding of the TJ protein composition and function is a rapidly advancing field. Major breakthroughs in the characterization of the TJ architec- ture came from the laboratory of the late Shoichiro Tsukita (1). Tsukita's group identified the first transmembrane protein components of the TJ: Occludin and a family of proteins named claudins. The first claudins were reported in 1998 (2). To date, 24 claudin isoforms have been identified, and the composition of particular claudin isoforms within a TJ seems to determine its paracellular transport properties. In the kidney, the different claudin isoforms are expressed in a nephron segment-specific pattern (3). The paracellular transport properties vary in these different segments of the nephron and correlate with the com- position of claudin isoforms in the TJ of the different nephron segments (4). For example, claudin-16 (also known as paracel- lin) is expressed in the TJ in the thick ascending limb and distal convoluted tubule and seems to mediate paracellular resorp- tion of both Mg 2 and Ca 2 . Mutations in claudin-16 are a cause of familial hypomagnesemia-hypercalciuria syndrome in humans (5).