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Claudin-10b is an important component of the tight junction in the thick ascending limb (TAL) of Henle's loop and allows paracellular sodium transport. In immunofluorescence stainings, claudin-10b-positive cells exhibited extensive extra staining of basolateral, column-like structures. The precise localization and function have so far remained elusive. In isolated cortical TAL segments from C57BL/6J mice, kidney-specific claudin-10 knockout mice (cKO), and respective litter mates (WT), we investigated the localization and protein expression and function by fluorescence microscopy and electrophysiological measurements. Ultrastructural analysis of TAL in kidney sections was performed by electron microscopy. Claudin-10b colocalized with the basolateral Na + -K + ATPase and the Cl - channel subunit barttin, but the lack of claudin-10b did not influence the localization or abundance of these proteins. However, the accessibility of the basolateral infolded extracellular space to ouabain or fluorescein was increased by basolateral Ca 2+ removal and in the absence of claudin-10b. Ultrastructural analysis by electron microscopy revealed a widening of basolateral membrane infoldings in cKO in comparison to WT. We hypothesize that claudin-10b shapes neighboring membrane invaginations by trans interaction to stabilize and facilitate high-flux salt transport in a water-tight epithelium., (© 2022 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of New York Academy of Sciences.)

Renal tubular transport mechanisms are optimized to be energy efficient and tailored to local gradients and transport rates. The combined transcellular action of ion channels, transporters, and pumps, together with the paracellular pathway, enables kidney function. Monogenetic diseases and mouse models indicate that both trans- and paracellular proteins can become disease-causing candidates and may be targets for future therapeutic approaches. Recent advances in tight junction research have provided new insights into their structure, function, and regulation. The thick ascending limb (TAL) is a nephron segment with specific requirements for the paracellular pathway. It has to fuel the generation of the corticomedullary concentration gradient, to be watertight, and to provide a highly selective permeability for Na + and divalent cations. Tight junction composition and function in the TAL is organized along the corticomedullary axis. Even on the level of a seemingly homogeneous tubular epithelium like the TAL, there is a separation of tight junction protein expression in the strands between the respective tricellular nexus of the junctional network. Here, we highlight some new insights from our recent work and that of others in this context. In addition, we provide some perspectives for the further study of paracellular transport mechanisms., (© 2017 New York Academy of Sciences.)

Calcium transport in the kidney is a key element in Ca(2+) homeostasis. Ca(2+) concentration, or more precisely the activity of freely dissociated Ca(2+) ions, is a prerequisite for the appropriate function of virtually every cell. Along the renal tubule, about 85% of the filtered Ca(2+) is transported across tight junctions at the paracellular route of reabsorption. Therefore, claudins, which form the conductive and selective part of the tight junctions, have moved into the focus of interest with respect to regulatory events in the control of Ca(2+) transport. This control is of particular interest for the kidney since it has to defend itself against nephrocalcinosis and kidney stones. Tight junction proteins provide pathways, driving forces, and regulatory targets for Ca(2+) transport. Direct regulation of tight junctions by changing Ca(2+) concentrations allows fast and efficient feedback loops to adapt Ca(2+) transport to the requirements of kidney function and plasma Ca(2+) concentration., (© 2012 New York Academy of Sciences.)

Tight junction (TJ) properties are determined by membrane protein complexes of neighboring cells that form both a barrier and a selective pathway for paracellular substrate transport. Our previous work supports the view that paracellular permeability changes in the thick ascending limb (TAL) may underlie the mechanism for familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), a rare autosomal recessive disease linked to mutations in claudin-16 (CLDN16) and claudin-19 (CLDN19). CLDN16 knockdown (KD) mice are lacking CLDN16 expression by transgenic RNA interference. We observed that the transport defect for Mg(2+) and Ca(2+) in this animal model is caused by a loss of paracellular cation selectivity. The permeability ratio for Na(+) over Cl(-) in KD mice was lower by a factor of two without a change in paracellular conductance, compared to wild type (WT). This resulted in a collapse of the transepithelial voltage, which is the driving force for Mg(2+) and Ca(2+) absorption in TAL. Since CLDN16 KD mice revealed lower blood pressure and an increased aldosterone plasma concentration, we hypothesize that the reduction in paracellular selectivity could allow backflow of Na(+) and Cl(-) into the lumen of the TAL, thus enhancing the distal NaCl load and challenging the organism with a latent NaCl loss.