Pediatr Nephrol (2011) 26:2133–2142 DOI 10.1007/s00467-011-1824-y EDUCATIONAL REVIEW Claudins in renal physiology and disease Jiahua Li & Wanwarat Ananthapanyasut & Alan S. L. Yu Received: 29 November 2010 / Revised: 26 January 2011 / Accepted: 28 January 2011 / Published online: 2 March 2011 # IPNA 2011 Abstract The tight junction forms the paracellular perme- ability barrier in all epithelia, including the renal tubule. Claudins are a family of tight junction membrane proteins with four transmembrane domains that form the para- cellular pore and barrier. Their first extracellular domain appears to be important for determining selectivity. A number of claudin isoforms have been found to be important in renal tubule function, both in adults and in neonates. Familial hypomagnesemic hypercalciuria with nephrocalcinosis is an autosomal recessive syndrome characterized by impaired reabsorption of Mg and Ca in the thick ascending limb of Henle's loop. Mutations in claudin-16 and 19 can both cause this syndrome, but the pathophysiological mechanism remains controversial. Keywords Tight junction . Claudin . Renal tubule . Paracellular . Transport . Calcium . Hypomagnesemia Introduction The renal tubule plays a major role in water and electrolyte homeostasis by mediating transepithelial reabsorption and secretion into the tubular fluid and hence regulating the final composition of urine. The route of transepithelial W. Ananthapanyasut : A. S. L. Yu (*) Division of Nephrology, Department of Medicine, University of Southern California, 2025 Zonal Avenue, RMR 406, Los Angeles, CA 90089, USA e-mail: alanyu@usc.edu J. Li : A. S. L. Yu Systems Biology and Disease Program, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA transport can be either transcellular (passing through cells and mediated by transmembrane channels, transporters and pumps) or paracellular (passing between adjacent epithelial cells). In contrast to transcellular transport, paracellular transport is always passive and so must be driven by an electrical or chemical gradient. Paracellular permeability of the renal tubule The magnitude and selectivity of paracellular permeability varies along the nephron. The proximal tubule is responsible for bulk reabsorption of salt and water. In the early proximal tubule, Na+ is reabsorbed transcellularly together with glucose, amino acids, and bicarbonate. This generates luminal fluid that is high in chloride and low in bicarbonate relative to the peritubular space. Because the late proximal tubule has a high paracellular permeability to both Na+ and Cl- but not to bicarbonate, Cl- diffuses paracellularly down its concentration gradient, generating a lumen-positive transepithelial voltage that then drives concomitant paracellular reabsorption of Na+ [1, 2]. Interestingly, the neonatal proximal straight tubule has a lower paracellular Cl- permeability than the adult tubule [3] and hence a lower rate of fluid reabsorption [4], which may predispose neonates to dehydration. In the thick ascending limb of Henle, Na+ is reabsorbed predominantly transcellularly via an apical Na-K-2Cl cotransporter and basolateral Na-K-ATPase. This generates a lumen-positive voltage by two mechanisms: (a) K+ reabsorbed across the apical membrane by the Na-K-2Cl cotransporter is recycled to the lumen through the K+ channel, ROMK; and (b) Na+ accumulated in the peri- tubular fluid back-leaks into the lumen via a paracellular pathway [5]. The paracellular route is also highly perme- able to divalent cations and so this lumen-positive potential