Physiological roles of claudins in kidney tubule paracellular transport

2017 ◽  
Vol 312 (1) ◽  
pp. F9-F24 ◽  
Author(s):  
Shigeaki Muto
Keyword(s):  
Tight Junctions ◽  
Water Movement ◽  
Current Knowledge ◽  
Paracellular Transport ◽  
Transepithelial Transport ◽  
Leaky Epithelia ◽  
Nephron Segments ◽  
Nephron Segment ◽  
Paracellular Pathways ◽  
Renal Tubular

The paracellular pathways in renal tubular epithelia such as the proximal tubules, which reabsorb the largest fraction of filtered solutes and water and are leaky epithelia, are important routes for transepithelial transport of solutes and water. Movement occurs passively via an extracellular route through the tight junction between cells. The characteristics of paracellular transport vary among different nephron segments with leaky or tighter epithelia. Claudins expressed at tight junctions form pores and barriers for paracellular transport. Claudins are from a multigene family, comprising at least 27 members in mammals. Multiple claudins are expressed at tight junctions of individual nephron segments in a nephron segment-specific manner. Over the last decade, there have been advances in our understanding of the structure and functions of claudins. This paper is a review of our current knowledge of claudins, with special emphasis on their physiological roles in proximal tubule paracellular solute and water transport.

Syncytial epithelia: transport in the absence of paracellular pathways

1983 ◽  
Vol 106 (1) ◽  
pp. 195-204
Author(s):  
R. B. Podesta
Keyword(s):  
Epithelial Transport ◽  
Apical Membrane ◽  
Electrical Coupling ◽  
Electrical Potential ◽  
Transepithelial Transport ◽  
Leaky Epithelia ◽  
Extrusion Mechanism ◽  
Paracellular Pathways ◽  
Nerve Muscle ◽  
Tight Epithelium

The syncytial epithelium of parasitic flatworms offers the opportunity to examine epithelial transport physiology in the absence of paracellular pathways. The asymmetric enzymatic and permeability properties of the apical and basal membranes confirm the transepithelial transport function of the syncytial epithelium. Although the absence of a paracellular pathway has led to the suggestion that the syncytium is a ‘tight’ epithelium, which would be consistent with its low osmotic and diffusive water permeability, the ion transport mechanisms in the apical membrane are more consistent with those predominating in ‘leaky’ epithelia. Contrary to that expected of an animal covered with a ‘tight’ epithelium, the parasitic flatworms are not good ion regulators. The apical membrane contains a Cl-:Na+ co-transport occurs by an active H+ extrusion mechanism, a large part of H+ secretion is coupled to Na+ influx as in ‘leaky’ will have to await electrical potential profile determinations which are made difficult by the electrical coupling of the syncytium to the underlying nerve-muscle syncytium.

scholarly journals Vibrodissociation method for isolation of defined nephron segments from human and rodent kidneys

2019 ◽  
Vol 317 (5) ◽  
pp. F1398-F1403 ◽  
Author(s):  
Elena Isaeva ◽  
Mykhailo Fedoriuk ◽  
Ruslan Bohovyk ◽  
Christine A. Klemens ◽  
Sherif Khedr ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Current Knowledge ◽  
Cell Types ◽  
Specific Cell ◽  
Renal Tubules ◽  
Gene Markers ◽  
Nephron Segments ◽  
Nephron Segment ◽  
Cell Energy ◽  
Health And Disease

Our current knowledge of the properties of renal ion channels responsible for electrolytes and cell energy homeostasis mainly relies on rodent studies. However, it has not been established yet to what extent their characteristics can be generalized to those of humans. The present study was designed to develop a standardized protocol for the isolation of well-preserved glomeruli and renal tubules from rodent and human kidneys and to assess the functional suitability of the obtained materials for physiological studies. Separation of nephron segments from human and rodent kidneys was achieved using a novel vibrodissociation technique. The integrity of isolated renal tubules and glomeruli was probed via electrophysiological analysis and fluorescence microscopy, and the purity of the collected fractions was confirmed using quantitative RT-PCR with gene markers for specific cell types. The developed approach allows rapid isolation of well-preserved renal tubules and glomeruli from human and rodent kidneys amenable for electrophysiological, Ca2+ imaging, and omics studies. Analysis of the basic electrophysiological parameters of major K+ and Na+ channels expressed in human cortical collecting ducts revealed that they exhibited similar biophysical properties as previously reported in rodent studies. Using vibrodissociation for nephron segment isolation has several advantages over existing techniques: it is less labor intensive, requires little to no enzymatic treatment, and produces large quantities of well-preserved experimental material in pure fractions. Applying this method for the separation of nephron segments from human and rodent kidneys may be a powerful tool for the indepth assessment of kidney function in health and disease.

Claudin Tight Junction Proteins: Novel Aspects in Paracellular Transport

2008 ◽  
Vol 28 (6) ◽  
pp. 577-584 ◽  
Author(s):  
Constanze Will ◽  
Michael Fromm ◽  
Dominik Müller
Keyword(s):  
Tight Junction ◽  
Solute Transport ◽  
Molecular Mechanisms ◽  
Family Members ◽  
Transport Processes ◽  
Paracellular Transport ◽  
Solute Flux ◽  
Solute Fluxes ◽  
Essential Components ◽  
Renal Tubular

Claudins are essential components of the intercellular tight junction and major determinants of paracellular solute fluxes across epithelia and endothelia. Many members of this family display a distinct charge or size specificity, whereas others render the epithelium impermeable to transport. Due to intercellular localization, claudin-mediated transport processes are passive and driven by an electrochemical gradient. In epithelial tissues, claudins exhibit a temporal–spatial expression pattern corresponding with regional and local solute transport profiles. Whereas paracellular transport mechanisms in organs such as intestine and kidney have been extensively investigated, little is known about the molecular mechanisms determining solute transport in the peritoneum, and thus the determinants of peritoneal dialysis. Given the ubiquitous expression of claudins in endothelia and epithelia, it is predictable that claudins also contribute to pore formation and determination in the peritoneum, and that they are involved in solute flux. Therefore, we review the basic characteristics of claudin family members and their function as exemplified in renal tubular transport and give an outlook to what extent claudin family members might be of importance for solute reabsorption across the peritoneal membrane.

Dependency of Microdissected Nephron Segments upon Oxidative Phosphorylation and Exogenous Substrates: A Relationship between Tubular Anatomical Location in the Kidney and Metabolic Activity

1989 ◽  
Vol 77 (3) ◽  
pp. 287-295 ◽  
Author(s):  
Shozo Torikai
Keyword(s):  
Collecting Duct ◽  
Anatomical Location ◽  
Thick Ascending Limb ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Nephron Segments ◽  
Henle's Loop ◽  
Renal Tubular ◽  
Substrate Deprivation ◽  
Exogenous Substrates

1. In order to examine the possibility of heterogeneity in the dependence of renal tubular cells upon oxidative phosphorylation and exogenous substrates, the effects of antimycin A and substrate deprivation on adenosine 5′-triphosphate (ATP) content were examined in isolated rat nephron segments in vitro at 37°C. 2. Antimycin A (5 μmol/l) caused varying decrements in cell ATP level within 5 min in the following order: proximal tubules > cortical thick ascending limb of Henle's loop (cTAL) > cortical collecting duct (cCD) in the cortex, and thin descending limb of Henle's loop (TDL) > medullary thick ascending limb of Henle's loop (mTAL) > outer medullary collecting duct (omCD) in the inner stripe of the outer medulla. In the thick ascending limb and the collecting duct, the segments located in the cortex were more sensitive than those in the medulla. 3. Substrate deprivation for 30 min markedly decreased the cell ATP content in cortical and medullary proximal tubules and also in medullary TDL, whereas it caused only a slight decrease in cTAL and mTAL with no change in cCD and omCD. 4. Media made hypertonic by the addition of 200 mmol/l NaCl under aerobic conditions, increased the requirement for exogenous substrates in TDL and mTAL, but not in omCD. This stimulation was seen to a lesser extent in media made hypertonic by the addition of mannitol instead of NaCl. 5. Taking into consideration a knowledge of rat kidney architecture and intrarenal gradient of oxygen partial pressure, it is likely that the observed dependency upon both oxygen and exogenous substrates in the renal tubular cells reflects adaptation of such cells to their anatomical location, and to the availability of those substances in situ. Furthermore, extracellular sodium concentration and osmolarity stimulate metabolic requirements to a different extent among the nephron segments.

scholarly journals Proximal and Distal Nephron-specific Adaptation to Furosemide

2021 ◽  
Author(s):  
Aram J. Krauson ◽  
Steven Schaffert ◽  
Elisabeth M. Walczak ◽  
Jonathan M. Nizar ◽  
Gwen M. Holdgate ◽  
...  
Keyword(s):  
Cell Number ◽  
Differentially Expressed ◽  
Sodium Reabsorption ◽  
Thick Ascending Limb ◽  
Distal Nephron ◽  
Transcriptional Responses ◽  
Cell Hyperplasia ◽  
Diuretic Resistance ◽  
Nephron Segments ◽  
Renal Tubular

ABSTRACTFurosemide, a widely prescribed diuretic for edema-forming states, inhibits sodium reabsorption in the thick ascending limb of the nephron. Tubular adaptation to diuretics has been observed, but the range of mechanisms along the nephron has not been fully explored. Using morphometry, we show that furosemide induces renal tubular epithelial hyperplasia selectively in distal nephron segments. By comparison, we find progressive cellular hypertrophy in proximal and distal nephron segments. We next utilize single cell RNA sequencing of vehicle- and furosemide-treated mice to define potential mechanisms of diuretic resistance. Consistent with distal tubular cell hyperplasia, we detect a net increase in DCT cell number and Birc5, an anti-apoptotic and pro-growth gene, in a subset of DCT cells, as the most prominently up-regulated gene across the nephron. We also map a gradient of cell-specific transcriptional changes congruent with enhanced distal sodium transport. Furosemide stimulates expression of the mitogen IGF-1. Thus, we developed a mouse model of inducible deletion of renal tubular IGF-1 receptor and show reduced kidney growth and proximal, but not distal, tubular hypertrophy by furosemide. Moreover, genes that promote enhanced bioavailability of IGF-1 including Igfbp1 and Igfbp5 are significantly and differentially expressed in proximal tubular segments and correspond to IGF-1R-dependent hypertrophy. In contrast, downstream PI3-kinase signaling genes including Pdk1, Akt1, Foxo3, FKBP4, Eif2BP4, and Spp1 are significantly and differentially expressed in distal nephron segments and correspond to IGF-1R-independent hypertrophy. These findings highlight novel mechanisms of tubular remodeling and diuretic resistance, provide a repository of transcriptional responses to a common drug, and expand the implications of long-term loop diuretic use for human disease.

Regional and segmental localization of AE2 anion exchanger mRNA and protein in rat kidney

1995 ◽  
Vol 269 (4) ◽  
pp. F461-F468 ◽  
Author(s):  
F. C. Brosius ◽  
K. Nguyen ◽  
A. K. Stuart-Tilley ◽  
C. Haller ◽  
J. P. Briggs ◽  
...  
Keyword(s):  
Collecting Duct ◽  
Rat Kidney ◽  
Chloride Concentration ◽  
Transepithelial Transport ◽  
Thick Ascending Limb ◽  
Cortical Collecting Duct ◽  
Base Exchange ◽  
Medullary Thick Ascending Limb ◽  
Nephron Segment ◽  
Medullary Collecting Duct

Chloride/base exchange activity has been detected in every mammalian nephron segment in which it has been sought. However, in contrast to the Cl-/HCO3- exchanger AE1 in type A intercalated cells, localization of AE2 within the kidney has not been reported. We therefore studied AE2 expression in rat kidney. AE2 mRNA was present in cortex, outer medulla, and inner medulla. Semiquantitative polymerase chain reaction of cDNA from microdissected tubules revealed AE2 cDNA levels as follows [copies of cDNA derived per mm tubule (+/- SE)]: proximal convoluted tubule, 688 +/- 161; proximal straight tubule, 652 +/- 189; medullary thick ascending limb, 1,378 +/- 226; cortical thick ascending limb, 741 +/- 24; cortical collecting duct, 909 +/- 71; and outer medullary collecting duct, 579 +/- 132. AE2 cDNA was also amplified in thin limbs and in inner medullary collecting duct. AE2 polypeptide was detected in all kidney regions. AE2 mRNA and protein were also detected in several renal cell lines. The data are compatible with the postulated roles of AE2 in maintenance of intracellular pH and chloride concentration and with its possible participation in transepithelial transport.

Self-Inhibition in Ca2+-Evoked Taste Responses: A Novel Tool for Functional Dissection of Salt Taste Transduction Mechanisms

1998 ◽  
Vol 79 (2) ◽  
pp. 911-921 ◽  
Author(s):  
Mamoun A. Kloub ◽  
Gerard L. Heck ◽  
John A. Desimone
Keyword(s):  
Tight Junctions ◽  
Ion Selectivity ◽  
Critical Concentration ◽  
Dependent Manner ◽  
High Concentration ◽  
Salt Taste ◽  
Cation Conductance ◽  
Taste Transduction ◽  
Transduction Mechanisms ◽  
Paracellular Pathways

Kloub, Mamoun A., Gerard L. Heck, and John A. DeSimone. Self-inhibition in Ca2+-evoked taste receptors: a novel tool for functional dissection of salt taste transduction mechanisms. J. Neurophysiol. 79: 911–921, 1998. Rat chorda tympani (CT) responses to CaCl2 were obtained during simultaneous current and voltage clamping of the lingual receptive field. Unlike most other salts, CaCl2 induced negatively directed transepithelial potentials and gave CT responses that were auto-inhibitory beyond a critical concentration. CT responses increased in a dose-dependent manner to ∼0.3 M, whereafter they decreased with increasing concentration. At concentrations where Ca2+ was self-inhibitory, it also inhibited responses to NaCl, KCl, and NH4Cl present in mixtures with CaCl2. Ca2+ completely blocked the amiloride-insensitive component of the NaCl CT response, the entire KCl-evoked CT response, and the high-concentration-domain CT responses of NH4Cl (≥0.3 M). The overlapping Ca2+-sensitivity between the responses of the three Cl− salts (Na+, K+, and NH+ 4) suggests a common, Ca2+-sensitive, transduction pathway. Extracellular Ca2+ has been shown to modulate the paracellular pathways in different epithelial cell lines by decreasing the water permeability and cation conductance of tight junctions. Ca2+-induced modulation of tight junctions is associated with Ca2+ binding to fixed negative sites. This results in a conversion of ion selectivity from cationic to anionic, which we also observed in our system through simultaneous monitoring of the transepithelial potential during CT recording. The data indicate the paracellular pathway as the stimulatory and modulatory site of CaCl2 taste responses. In addition, they indicate that important transduction sites for NaCl, KCl, and NH4Cl taste reception are accessible only through the paracellular pathways. More generally, they show that modulation of paracellular transport by Ca2+ in an intact epithelium has functional consequences at a systemic level.

scholarly journals Atlas of gene expression in the mouse kidney: new features of glomerular parietal cells

2011 ◽  
Vol 43 (3) ◽  
pp. 161-173 ◽  
Author(s):  
Lydie Cheval ◽  
Fabien Pierrat ◽  
Carole Dossat ◽  
Mathieu Genete ◽  
Martine Imbert-Teboul ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mouse Kidney ◽  
Thick Ascending Limb ◽  
Proliferating Cells ◽  
Quantitative Expression ◽  
Nephron Segments ◽  
Nephron Segment ◽  
Mrna Markers ◽  
Insight Into

To gain molecular insight into kidney function, we performed a high-resolution quantitative analysis of gene expression in glomeruli and nine different nephron segments dissected from mouse kidney using Serial Analysis of Gene Expression (SAGE). We also developed dedicated bioinformatics tools and databases to annotate mRNA tags as transcripts. Over 800,000 mRNA SAGE tags were sequenced corresponding to >20,000 different mRNA tags present at least twice in at least one library. Hierarchical clustering analysis of tags demonstrated similarities between the three anatomical subsegments of the proximal tubule, between the cortical and medullary segments of the thick ascending limb of Henle's loop, and between the three segments constituting the aldosterone-sensitive distal nephron segments, whereas the glomerulus and distal convoluted tubule clusterized independently. We also identified highly specific mRNA markers of each subgroup of nephron segments and of most nephron segments. Tag annotation also identified numbers of putative antisense mRNAs. This database constitutes a reference resource in which the quantitative expression of a given gene can be compared with that of other genes in the same nephron segment, or between different segments of the nephron. To illustrate possible applications of this database, we performed a deeper analysis of the glomerulus transcriptome that unexpectedly revealed expression of several ion and water carriers; within the glomerulus, they were found to be preferentially expressed in the parietal sheet. It also revealed the major role of the zinc finger transcription factor Wt1 in the specificity of gene expression in the glomerulus. Finally, functional annotation of glomerulus-specific transcripts suggested a high proliferation activity of glomerular cells. Immunolabeling for PCNA confirmed a high percentage of proliferating cells in the glomerulus parietal sheet.

Functional segmentation of the mammalian nephron

1981 ◽  
Vol 241 (3) ◽  
pp. F203-F218 ◽  
Author(s):  
H. R. Jacobson
Keyword(s):  
Biochemical Analysis ◽  
Epithelial Transport ◽  
Cell Types ◽  
Transport Processes ◽  
Renal Physiology ◽  
Hormonal Responses ◽  
Nephron Segments ◽  
New Information ◽  
Nephron Segment

Although each of the major experimental techniques applied to the study of renal physiology has provided its fair share of new information, the technique of in vitro microperfusion of nephron segments is notable for two major contributions. First, it has supplied a more direct and controlled means of studying epithelial transport processes, some of which already have helped us to understand certain aspects of kidney function and others of which have yet to find their application in unraveling the mysteries of the kidney. Second, in the process of delineating these transport characteristics, it has served to emphasize the epithelial specialization present in the kidney, providing functional counterparts to the already recognized anatomic heterogeneity present in the kidney. In this second role microperfusion has spawned the application of biochemical analysis of the hormonal responses of various nephron segments and contributed to the impetus for work in culturing the various cell types present in each nephron segment. This review outlines the functional characteristics of the 11 major segments of the nephron, incorporating what has been learned from some of the biochemical work on hormone response and correlating the latter with transport events.

scholarly journals Hippo signaling in the kidney: the good and the bad

2016 ◽  
Vol 311 (2) ◽  
pp. F241-F248 ◽  
Author(s):  
Jenny S. Wong ◽  
Kristin Meliambro ◽  
Justina Ray ◽  
Kirk N. Campbell
Keyword(s):  
Embryonic Development ◽  
Current Knowledge ◽  
Hippo Pathway ◽  
Hippo Signaling ◽  
Filtration Barrier ◽  
Signaling Axis ◽  
Kinase Cascade ◽  
Barrier Regulation ◽  
Renal Tubular ◽  
The Hippo Pathway

The Hippo signaling pathway is an evolutionarily conserved kinase cascade, playing multiple roles in embryonic development that controls organ size, cell proliferation, and apoptosis. At the center of this network lie the Hippo kinase target and downstream pathway effector Yes-associated protein (YAP) and its paralog TAZ. In its phosphorylated form, cytoplasmic YAP is sequestered in an inactive state. When it is dephosphorylated, YAP, a potent oncogene, is activated and relocates to the nucleus to interact with a number of transcription factors and signaling regulators that promote cell growth, differentiation, and survival. The identification of YAP activation in human cancers has made it an attractive target for chemotherapeutic drug development. Little is known to date about the function of the Hippo pathway in the kidney, but that is rapidly changing. Recent studies have shed light on the role of Hippo-YAP signaling in glomerular and lower urinary tract embryonic development, maintenance of podocyte homeostasis, the integrity of the glomerular filtration barrier, regulation of renal tubular cyst growth, renal epithelial injury in diabetes, and renal fibrogenesis. This review summarizes the current knowledge of the Hippo-YAP signaling axis in the kidney under normal and disease conditions.

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