Claudins and nephrolithiasis

Purpose of review The greatest risk factor for kidney stone formation is increased urinary calcium excretion. Most filtered calcium is reabsorbed from the proximal tubule and the thick ascending limb (TAL) of Henle's loop via a paracellular pathway. Claudins are tight junction proteins that confer the permeability properties of an epithelium. We review the contribution of renal claudins to nephron calcium permeability and how perturbations in these pathways cause alterations in tubular calcium transport, hypercalciuria, nephrocalcinosis, or nephrolithiasis. Recent findings Claudin-16 and Claudin-19 form a complex with claudin-3 enabling divalent cation permeability in the TAL. Claudin-14 interacts with claudin-16 to attenuate calcium permeability through this pore. Intronic mutations in claudin-14 increase expression causing hypercalciuria and kidney stones. A different type of TAL tight junction pore is composed of claudin-10b, which does not preferentially permeate calcium. Deletion of claudin-10b results in increased expression of the claudin-16/claudin-19 complex expressed in the medullary TAL and nephrocalcinosis. Summary Alterations to claudins expressed in the TAL tight junction greatly affects calcium homeostasis as highlighted by point mutations in claudin-16 or claudin-19 causing FHHNC or gain of function mutations in claudin-14 causing kidney stones.

• Publication year

  2018

• Venue

  Current opinion in nephrology and hypertension

• Publication date

  2018-07-01

• Fields of study

  Medicine

• Identifiers
  DOI 10.1097/MNH.0000000000000426PMID 29782346
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Claudin‐2‐mediated cation and water transport share a common pore

  2017cited by this paper
• Deletion of claudin-10 rescues claudin-16-deficient mice from hypomagnesemia and hypercalciuria.

  2017cited by this paper
• A variant in a cis‐regulatory element enhances claudin‐14 expression and is associated with pediatric‐onset hypercalciuria and kidney stones

  2017cited by this paper
• Calcium-Sensing Receptor Genetic Polymorphisms and Risk of Developing Nephrolithiasis in a Chinese Population

  2017cited by this paper
• Crystal structures of claudins: insights into their intermolecular interactions

  2017cited by this paper
• Parathyroid hormone controls paracellular Ca2+ transport in the thick ascending limb by regulating the tight-junction protein Claudin14

  2017cited by this paper
• Epidemiology and economics of nephrolithiasis

  2017cited by this paper
• Corticomedullary difference in the effects of dietary Ca2+ on tight junction properties in thick ascending limbs of Henle’s loop

  2016cited by this paper
• Claudin‐16 Deficiency Impairs Tight Junction Function in Ameloblasts, Leading to Abnormal Enamel Formation

  2016cited by this paper
• Mosaic expression of claudins in thick ascending limbs of Henle results in spatial separation of paracellular Na+ and Mg2+ transport

  2016cited by this paper
• Acidosis and Urinary Calcium Excretion: Insights from Genetic Disorders.

  2016cited by this paper
• Common and rare variants associated with kidney stones and biochemical traits

  2015cited by this paper
• Assembly and function of claudins: Structure-function relationships based on homology models and crystal structures.

  2015cited by this paper
• Claudins and the kidney.

  2015cited by this paper
• Polymorphisms in CaSR and CLDN14 Genes Associated with Increased Risk of Kidney Stone Disease in Patients from the Eastern Part of India

  2015cited by this paper
• Epigenetic regulation of microRNAs controlling CLDN14 expression as a mechanism for renal calcium handling.

  2015cited by this paper
• KLHL3 regulates paracellular chloride transport in the kidney by ubiquitination of claudin-8

  2015cited by this paper
• Diabetic severity and risk of kidney stone disease.

  2014cited by this paper
• Kidney stones and cardiovascular events: a cohort study.

  2014cited by this paper
• Paracellular calcium transport across renal and intestinal epithelia.

  2014cited by this paper
• Claudin-14 underlies Ca⁺⁺-sensing receptor-mediated Ca⁺⁺ metabolism via NFAT-microRNA-based mechanisms.

  2014cited by this paper
• PNAS Plus Significance Statements

  2014cited by this paper
• Fluid reabsorption in proximal convoluted tubules of mice with gene deletions of claudin-2 and/or aquaporin1.

  2013cited by this paper
• Activation of the Ca(2+)-sensing receptor increases renal claudin-14 expression and urinary Ca(2+) excretion.

  2013cited by this paper
• In tight junctions, claudins regulate the interactions between occludin, tricellulin and marvelD3, which, inversely, modulate claudin oligomerization

  2013cited by this paper
• Proximal tubular NHEs: sodium, protons and calcium?

  2013cited by this paper
• Calcium-sensing receptor (CaSR): pharmacological properties and signaling pathways.

  2013cited by this paper
• Prevalence of kidney stones in the United States.

  2012cited by this paper
• Claudin-17 forms tight junction channels with distinct anion selectivity

  2012cited by this paper
• Claudin-4 Deficiency Results in Urothelial Hyperplasia and Lethal Hydronephrosis

  2012cited by this paper
• The epithelial sodium/proton exchanger, NHE3, is necessary for renal and intestinal calcium (re)absorption.

  2012cited by this paper
• Deletion of claudin-10 (Cldn10) in the thick ascending limb impairs paracellular sodium permeability and leads to hypermagnesemia and nephrocalcinosis

  2012cited by this paper
• Claudin‐14 regulates renal Ca++ transport in response to CaSR signalling via a novel microRNA pathway

  2012cited by this paper
• Claudin-4 forms a paracellular barrier, revealing the interdependence of claudin expression in the loose epithelial cell culture model opossum kidney cells.

  2012cited by this paper
• Phenotypic variability of CLDN14 mutations causing DFNB29 hearing loss in the Pakistani population

  2012cited by this paper
• Kidney stones and kidney function loss: a cohort study

  2012cited by this paper
• Chronic kidney disease in kidney stone formers.

  2011cited by this paper
• Claudin-2–deficient mice are defective in the leaky and cation-selective paracellular permeability properties of renal proximal tubules

  2010cited by this paper
• Differential expression of claudin tight junction proteins in the human cortical nephron

  2010cited by this paper
• Claudin-2, a component of the tight junction, forms a paracellular water channel

  2010cited by this paper
• Association between calcium-sensing receptor gene polymorphisms and recurrent calcium kidney stone disease: A comprehensive gene analysis

  2010cited by this paper
• Targeted deletion of murine Cldn16 identifies extra- and intrarenal compensatory mechanisms of Ca2+ and Mg2+ wasting.

  2010cited by this paper
• Claudin-3 acts as a sealing component of the tight junction for ions of either charge and uncharged solutes.

  2010cited by this paper
• Kidney stones associate with increased risk for myocardial infarction.

  2010cited by this paper
• Molecular Basis for Cation Selectivity in Claudin-2–based Paracellular Pores: Identification of an Electrostatic Interaction Site

  2009cited by this paper
• Kidney stones and the risk for chronic kidney disease.

  2009cited by this paper
• Claudin-10 exists in six alternatively spliced isoforms that exhibit distinct localization and function

  2009cited by this paper
• Sequence variants in the CLDN14 gene associate with kidney stones and bone mineral density

  2009cited by this paper
• Claudin-16 and claudin-19 interact and form a cation-selective tight junction complex.

  2008cited by this paper
• Tight junction proteins claudin-2 and -12 are critical for vitamin D-dependent Ca2+ absorption between enterocytes.

  2008cited by this paper
• Renal localization and function of the tight junction protein, claudin-19.

  2007cited by this paper
• R990G polymorphism of calcium-sensing receptor does produce a gain-of-function and predispose to primary hypercalciuria.

  2007cited by this paper
• Two splice variants of claudin-10 in the kidney create paracellular pores with different ion selectivities.

  2006cited by this paper
• Na+ Recirculation and Isosmotic Transport

  2006cited by this paper
• Mutations in the tight-junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement.

  2006cited by this paper
• Claudins 6, 9, and 13 are developmentally expressed renal tight junction proteins.

  2006cited by this paper
• Urologic diseases in America project: urolithiasis.

  2005cited by this paper
• Differential expression of claudin‐2 along the human intestine: Implication of GATA‐4 in the maintenance of claudin‐2 in differentiating cells

  2005cited by this paper
• Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5.

  2003cited by this paper
• Claudin 14 knockout mice, a model for autosomal recessive deafness DFNB29, are deaf due to cochlear hair cell degeneration.

  2003cited by this paper
• Association between activating mutations of calcium-sensing receptor and Bartter's syndrome.

  2002cited by this paper
• Differential expression patterns of claudins, tight junction membrane proteins, in mouse nephron segments.

  2002cited by this paper
• Functional characterization of a calcium-sensing receptor mutation in severe autosomal dominant hypocalcemia with a Bartter-like syndrome.

  2002cited by this paper
• Identification and characterization of a gene with base substitutions associated with the absorptive hypercalciuria phenotype and low spinal bone density.

  2002cited by this paper
• Claudin-2 expression induces cation-selective channels in tight junctions of epithelial cells

  2002cited by this paper
• Influence of calcium-sensing receptor gene on urinary calcium excretion in stone-forming patients.

  2002cited by this paper
• Claudin-2 is selectively expressed in proximal nephron in mouse kidney.

  2001cited by this paper
• Heterogeneity in expression and subcellular localization of claudins 2, 3, 4, and 5 in the rat liver, pancreas, and gut.

  2001cited by this paper
• Mutations in the gene encoding tight junction claudin-14 cause autosomal recessive deafness DFNB29.

  2001cited by this paper
• Extracellular calcium sensing and extracellular calcium signaling.

  2001cited by this paper
• A novel activating mutation in calcium-sensing receptor gene associated with a family of autosomal dominant hypocalcemia.

  1999cited by this paper
• Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption.

  1999cited by this paper
• Renal and intestinal absorptive defects in mice lacking the NHE3 Na +/H+ exchanger

  1998cited by this paper
• Defective proximal tubular fluid reabsorption in transgenic aquaporin-1 null mice.

  1998cited by this paper
• Expression and Characterization of Inactivating and Activating Mutations in the Human Ca2+o-sensing Receptor*

  1996cited by this paper
• Ambulatory evaluation of nephrolithiasis: an update of a 1980 protocol.

  1995cited by this paper
• Calcium handling by the mammalian kidney.

  1993cited by this paper
• Effects of PTH, calcitonin, and cAMP on calcium transport in rabbit distal nephron segments.

  1990cited by this paper
• Basolateral cell membrane Ca-Na exchange in single rabbit connecting tubules.

  1990cited by this paper
• Calcium transport by the proximal tubule.

  1986cited by this paper
• Microelectrode assessment of chloride-conductive properties of cortical collecting duct.

  1984cited by this paper
• Electrophysiological properties of cellular and paracellular conductive pathways of the rabbit cortical collecting duct

  1984cited by this paper
• Calcium transport in the rabbit superficial proximal convoluted tubule.

  1984cited by this paper
• Voltage-dependent calcium movement across the cortical collecting duct.

  1982cited by this paper
• Sites of hormone action in the mammalian nephron.

  1981cited by this paper
• Effects of parathyroid hormone and N6,O2′-dibutyryl cyclic AMP on Ca2+ transport across the rabbit distal nephron segments perfused in vitro

  1981cited by this paper
• Calcium transport in the pars recta and thin descending limb of Henle of the rabbit, perfused in vitro.

  1980cited by this paper
• Subcellular changes in rat hearts perfused with potassium-free medium.

  1979cited by this paper
• Calcium transport across segments of the rabbit distal nephron in vitro.

  1978cited by this paper
• Factors governing the transepithelial potential difference across the proximal tubule of the rat kidney.

  1974cited by this paper
• Proximal Tubule Potential Difference. DEPENDENCE ON GLUCOSE, HCO3, AND AMINO ACIDS

  1973cited by this paper
• Phenomenologic description of Na+, Cl− and HCO3− absorption from proximal tubules of the rat kidney

  1973cited by this paper
• Proximal tubule potential difference. Dependence on glucose on glucose, HCO 3 , and amino acids.

  1973cited by this paper
• Solvent drag on non-electrolytes during osmotic flow through isolated toad skin and its response to antidiuretic hormone.

  1957cited by this paper

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• Understanding Rare Kidney Stone Diseases: A Review.

  2025cites this paper
• Molecular insights into cell signaling pathways in kidney stone formation

  2025cites this paper
• Exploring the Critical Role of Tight Junction Proteins in Kidney Disease Pathogenesis

  2024cites this paper
• Tight junctions and acute kidney injury

  2023cites this paper
• Integrated single-nucleus sequencing and spatial architecture analysis identified distinct injured-proximal tubular types in calculi rats

  2023cites this paper
• Tight junction and kidney stone disease

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• Childhood nephrolithiasis and nephrocalcinosis caused by metabolic diseases and renal tubulopathy

  2022cites this paper
• Claudins in kidney health and disease

  2022cites this paper
• Mutations in CLDN2 Are Not a Common Cause of Pediatric Idiopathic Hypercalciuria in Canada

  2022cites this paper
• Monogenic causation of pediatric nephrolithiasis

  2022influential citation
• Tumor Necrosis Factor-α Induces Claudin-3 Upregulation in Kidney Tubular Epithelial Cells through NFκB and CREB1.

  2021cites this paper
• Claudin-2 and claudin-12 form independent, complementary pores required to maintain calcium homeostasis

  2021cites this paper
• Molecular mechanisms altering tubular calcium reabsorption

  2021influential citation
• Introduction à la physiologie rénale

  2021cites this paper
• Channel functions of claudins in the organization of biological systems.

  2020cites this paper
• Use of whole-exome sequencing to identify a novel ADCY10 mutation in a patient with nephrolithiasis.

  2020cites this paper
• Fundamentals of Epithelial Na+ Absorption

  2020cites this paper
• Claudin-7b and Claudin-h are required for controlling cilia morphogenesis in the zebrafish kidney.

  2019cites this paper
• TRPV5 in renal tubular calcium handling and its potential relevance for nephrolithiasis.

  2019cites this paper
• Temporal Effects of Quercetin on Tight Junction Barrier Properties and Claudin Expression and Localization in MDCK II Cells

  2019cites this paper
• Nephrolithiasis secondary to inherited defects in the thick ascending loop of henle and connecting tubules

  2018cites this paper
• Inching toward a Greater Understanding of Genetic Hypercalciuria: The Role of Claudins.

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