Pediatr Nephrol (2011) 26:2133–2142 The latter then acts as the driving force for paracellular reabsorption of Na, which thereby accounts for one-third of Na reabsorption in this segment [2]. The localization and properties of claudin-2 suggest that it is the pore protein that mediates this process. Consistent with this, the S2 segments of claudin-2 knockout mice proximal tubules exhibit decreased Na and Cl reabsorption [18]. Moreover, the mice have higher fractional excretions of Na and Cl after NaCl infusion. There is also data to suggest that claudin-2 is permeable to other monovalent cations, including K+, and to a lesser extent to calcium [21]. A recent study also showed that it is permeable to water [53]. K+ and calcium are thought to be reabsorbed paracellularly in the proximal tubule. Whether water also permeates through the paracellular pathway has historically been controversial, especially since most water reabsorption is now known to pass transcellularly through aquaporin water channels. The in vitro data suggest that all of these substances can indeed be reabsorbed paracellularly and that claudin-2 is responsible. Claudin-7 Claudin-7 is expressed in the distal convoluted tubule, connecting segment and collecting duct [54, 55]. In vitro data on its functional properties are somewhat contradicto- ry. Overexpression studies in LLC-PK cells suggested that claudin-7 acts as a Cl barrier and a Na pore [55]. However, knockdown studies in MDCK cells suggested instead that claudin-7 acts as a Cl pore and a Na barrier [56]. Mice with knockout mice exhibit renal NaCl wasting and secondary hyperaldosteronism [57]. This suggests that claudin-7 is necessary in some way for maximum reabsorption of NaCl in the distal nephron. Claudin-6 and -9 Neonatal proximal tubules have a lower capacity for fluid reabsorption than the adult proximal tubule. This is in part attributable to a lower passive paracellular permeability to chloride ions and higher resistance compared to that of adult proximal tubules [3]. Abuazza et al. showed that claudin-6, claudin-9, and claudin-13 were selectively expressed in the neonatal mouse kidney [58]. In adult kidneys, claudin-6 was expressed at relatively low levels while claudins-9 and -13 were absent. Claudin-6 and -9 were present in neonatal proximal convoluted tubules. Furthermore, when claudins-6 and -9 were transfected into Madin–Darby canine kidney II (MDCK II) cells, they each caused an increase in trans- epithelial resistance and decrease in Cl permeability, suggesting that they contribute to the limited reabsorption capacity of neonatal proximal tubules [59]. 2139 Conclusions In conclusion, it is now well established that claudins form the paracellular barrier and pore in epithelia. The role of the first extracellular domain in lining the pore and determining the selectivity of paracellular permeation is also firmly established, and the roles of specific residues in this domain and the biophysical basis for selectivity are beginning to be elucidated. For a handful of claudin isoforms, there is now information about their physiological role in regulating tubule transport of fluid and electrolytes in the kidney, but there are still many isoforms for which no such information is available. The rare monogenic syndrome of FHHNC has provided an opportunity to understand the role of claudins in the function of the thick ascending limb of Henle. So far, however, the only polygenic renal disorder that has been associated with claudin gene variants is kidney stone disease. Importantly, there has been very little investigation into the mechanisms that regulate renal claudins, and their potential involvement in acquired kidney diseases, and we anticipate that this will be a particularly fertile area for future research. Multiple choice questions (answers appear following the reference list) 1: Which of the following best describes paracellular permeability and transport in the late proximal tubule? A. The proximal tubule has a high transepithelial resistance and acts as a barrier to small ions. B. NaCl is reabsorbed paracellularly, driven by the Cl concentration gradient. C. Organic anions are secreted across the paracellular pathway. D. Water is predominantly reabsorbed via the para- cellular pathway, driven by the osmotic gradient. E. The proximal tubule is selectively permeable to bicarbonate which is reabsorbed paracellularly. 2: Which domain of the claudin protein forms the lining of the paracellular pore? A. Amino terminal B. Carboxy terminal C. 1st transmembrane domain D. 1st extracellular domain E. Cytosolic loop between 2nd and 3rd transmem- brane domain 3: It has been shown that D65 (aspartate residue at position 65) in claudin-2 is a cation-binding site that is responsible for its cation-selectivity. Which of the following mutation of claudin-2 would be most likely to turn claudin-2 from a cation-selective pore to an anion-selective pore?