Significant water absorption goes paracellular in kidney proximal tubules

Field: Medicine (Health Sciences)

Editorial FociSignificant water absorption goes paracellular in kidney proximal tubulesRita Rosenthal, and Michael FrommRita RosenthalInstitute of Clinical Physiology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany, and Michael FrommInstitute of Clinical Physiology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, GermanyPublished Online:01 Jan 2014https://doi.org/10.1152/ajprenal.00545.2013This is the final version - click for previous versionMoreSectionsPDF (49 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations it had been a fundamental dispute for several decades, whether water passes epithelia such as kidney proximal tubule or small intestine along the transcellular, paracellular, or both pathways.By discovery of the transmembranal aquaporin water channels (AQP), the molecular basis of the transcellular pathway was uncovered (1), but the molecular basis of the tight junctional pathway was not resolved at that time. Transcellular and paracellular water transport was, therefore, measured by methods that attempted to technically discriminate the two pathways. This turned out to be difficult, and as a result, the contribution of the paracellular pathway was estimated in the maximal range between 0 and 100%, depending on the method used for analysis (3).In recent years, several tight junction proteins were identified to form paracellular channels with selectivity for small cations (claudin-2, claudin-10b, and claudin-15) or anions (claudin-10a and claudin-17) (4). In consequence, new approaches were developed to measure transepithelial water transport before and after molecular perturbation of the tight junction by overexpression or downregulation of specific junctional proteins. In this way, the tight junctional contribution to transepithelial water transport could be analyzed.Using an overexpression study in the epithelial cell line MDCK-C7, Rosenthal et al. (8) identified claudin-2 to form a paracellular water channel. Claudin-2 is highly expressed in the proximal tubule of the kidney and is known as a paracellular cation channel (2). Thus, claudin-2 forms channels for both, small cations and water. Whereas this in vitro study employed claudin-2 overexpression, others were performed on claudin-2-deficient mice.In a very evident study published in the American Journal of Physiology—Renal Physiology, Schnermann et al. (9) measured proximal fluid reabsorption in wild-type mice and mice deficient for claudin-2, AQP-1, and both. In claudin-2-deficient mice, fluid reabsorption was reduced by 23% compared to wild-type mice. This result corroborates the concept of a claudin-2-based paracellular water permeability and convincingly demonstrates a paracellular contribution to proximal tubule fluid reabsorption of 25%. Schnermann et al. (9) performed a comprehensive analysis not only of proximal fluid reabsorption, but also on kidney and single-nephron filtration rate on a large number of mice. Furthermore, in a detailed expression analysis of wild-type mice and mice deficient for claudin-2, AQP1, and both, the authors demonstrated that the findings are due to the deletion of the specific protein and not to further alterations in gene expression.They showed that in mice deficient of AQP-1, which is highly expressed in both apical and basolateral membranes of proximal tubule cells and, thus, represents the main pathway for transcellular water movement, fluid reabsorption is reduced by 20%. The absence of AQP-1 causes a transepithelial osmotic difference, which induces fluid reabsorption across AQP1-independent transcellular pathways. This was observed both in the absence and presence of claudin-2. In mice deficient of both AQP-1 and claudin-2, a reduction of fluid flow by 26% was found, which was not significantly different from values measured in singly deficient animals (9). This was an unexpected finding of the study, which has not be sufficiently explained yet. A possible interpretation could be the assumption that AQP-1- and claudin-2-mediated water fluxes are interdependent, as it has been shown for paracellular permeability and AQP-5 function in salivary glands (5).These findings are consistent with results obtained by Muto et al. (7), who found a decreased net transepithelial reabsorption of Na, Cl, and water in isolated, perfused S2 segments of proximal tubules of claudin-2-deficient mice. Aquaporin expression was not investigated in that study. Proximal tubule net water reabsorption in Cldn2−/− mice was decreased by about 30% compared with that in Cldn2+/+ mice.A possible alternative explanation for the role of claudin-2 in kidney tubular water flux has to be discussed, namely, that claudin-2 mediates Na+ reabsorption through the paracellular pathway, but water follows only along the transcellular pathway, mediated, e.g., by AQP-1. However, this possibility was excluded in the study on MDCK C7 cells, as it demonstrated that in claudin-2-expressing cell layers, water flux was induced not only by an osmotic gradient, but also by a NaCl gradient in the absence of an osmotic gradient. As a second piece of evidence, net water flux induced by an osmotic gradient caused a net Na+ transport in claudin-2-expressing cells, indicating that water and Na+ were transported through the same channel (8).For claudin-2-based paracellular channels, the characteristics of the pore have been determined. A negatively charged site within the pore formed by aspartate-65 causes the cation selectivity by electrostatic interaction. The pore radius was estimated to be 3.25 Å, which appears large enough for the passage of both partially dehydrated cations and water molecules (diameter 2.8 Å) (10).Among other claudins exhibiting undisputed cation or anion permeability (4), neither overexpression of claudin-10b nor of claudin-17 altered water permeability of MDCK C7 cell layers (6, 8). Thus, claudin-2 so far is the only claudin for which water permeability has been demonstrated. The present study by Schnermann et al. (9) has convincingly proven and quantified that concept for kidney proximal tubules.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the authors.AUTHOR CONTRIBUTIONSAuthor contributions: R.R. and M.F. drafted manuscript; R.R. and M.F. edited and revised manuscript; R.R. and M.F. approved final version of manuscript.REFERENCES1. 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J Cell Sci 123: 1913–1921, 2010.Crossref | PubMed | ISI | Google Scholar9. Schnermann J, Huang Y, Mizel D. Fluid reabsorption in proximal convoluted tubules of mice with gene deletions of claudin-2 and/or aquaporin. Am J Physiol Renal Physiol 305: F1352–F1364, 2013.Link | ISI | Google Scholar10. Yu ASL, Cheng MH, Angelow S, Günzel D, Kanzawa SA, Schneeberger EE, Fromm M, Coalson RD. Molecular basis for cation selectivity in claudin-2-based paracellular pores: Identification of an electrostatic interaction site. J Gen Physiol 133: 111–127, 2009.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: M. Fromm, Institute of Clinical Physiology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany (e-mail: michael.[email protected]de). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation More from this issue > Volume 306Issue 1January 2014Pages F51-F52 Copyright & PermissionsCopyright © 2014 the American Physiological Societyhttps://doi.org/10.1152/ajprenal.00545.2013PubMed24154692History Received 11 October 2013 Accepted 16 October 2013 Published online 1 January 2014 Published in print 1 January 2014 Metrics