Deletion of
            <i>claudin-10</i>
            (
            <i>Cldn10</i>
            ) in the thick ascending limb impairs paracellular sodium permeability and leads to hypermagnesemia and nephrocalcinosis

Breiderhoff, Tilman; Himmerkus, Nina; Stuiver, Marchel; Mutig, Kerim; Will, Constanze; Meij, Iwan C.; Bachmann, S.; Bleich, Markus; Willnow, Thomas E.; Müller, Dominik

doi:10.1073/pnas.1203834109

Cited by 134 publications

(170 citation statements)

References 26 publications

Supporting

Mentioning

155

Contrasting

Unclassified

Order By: Relevance

“…Furthermore, it fits well with the observation that the absence of cldn10b from the TAL led to decreased paracellular Na + permeability in mice (12).…”

Section: Discussionsupporting

confidence: 73%

“…It seems reasonable that the loss of cldn10b from TJs in the TAL allows the TJs to be occupied by the other claudins present. The observed insertion of cldn3/16/19 in nearly all TJs in the cortex/OSOM could contribute to the hyperabsorption of Ca 2+ and Mg 2+ observed in these animals (12). Conversely, the absence of cldn16 alone from TJs in the TAL did not result in the redistribution of cldn10b.…”

Section: Discussionmentioning

confidence: 86%

“…Whereas cldn3, cldn10, cldn16, and cldn19 were clearly expressed, cldn11 could not be detected. The anti-cldn10 antibody cannot discriminate between isoforms a and b, but PCR showed that only cldn10b is present in the TAL (10,12). Thus, a positive cldn10 staining in the TAL is considered to indicate the presence of the isoform cldn10b.…”

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Mosaic expression of claudins in thick ascending limbs of Henle results in spatial separation of paracellular Na ⁺ and Mg ²⁺ transport

Milatz

Himmerkus

Wulfmeyer

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

181

View full text Add to dashboard Cite

The thick ascending limb (TAL) of Henle's loop drives paracellular Na + , Ca 2+ , and Mg 2+ reabsorption via the tight junction (TJ). The TJ is composed of claudins that consist of four transmembrane segments, two extracellular segments (ECS1 and -2), and one intracellular loop. Claudins interact within the same (cis) and opposing (trans) plasma membranes. The claudins Cldn10b, -16, and -19 facilitate cation reabsorption in the TAL, and their absence leads to a severe disturbance of renal ion homeostasis. We combined electrophysiological measurements on microperfused mouse TAL segments with subsequent analysis of claudin expression by immunostaining and confocal microscopy. Claudin interaction properties were examined using heterologous expression in the TJ-free cell line HEK 293, live-cell imaging, and Förster/FRET. To reveal determinants of interaction properties, a set of TAL claudin protein chimeras was created and analyzed. Our main findings are that (i) TAL TJs show a mosaic expression pattern of either cldn10b or cldn3/cldn16/cldn19 in a complex; (ii) TJs dominated by cldn10b prefer Na + over Mg 2+ , whereas TJs dominated by cldn16 favor Mg 2+ over Na + ; (iii) cldn10b does not interact with other TAL claudins, whereas cldn3 and cldn16 can interact with cldn19 to form joint strands; and (iv) further claudin segments in addition to ECS2 are crucial for trans interaction. We suggest the existence of at least two spatially distinct types of paracellular channels in TAL: a cldn10b-based channel for monovalent cations such as Na + and a spatially distinct site for reabsorption of divalent cations such as Ca 2+ and Mg 2+ .T he kidney regulates the salt and water balance of the body by filtration and subsequent reabsorption or secretion of ions and water. Thereby it controls blood pressure and maintains acid-base homeostasis. The thick ascending limb (TAL) of Henle's loop drives reabsorption of Na + , Cl − , Ca 2+ , and Mg 2+ from the tubular fluid into the blood. Na + and Cl − are reabsorbed via the transcellular pathway, involving the renal-specific isoform of the Na + /K + /2Cl − cotransporter (NKCC2) in the apical epithelial cell membrane and Na + /K + -ATPase and chloride channel ClC-Kb in the basolateral membrane. K + is circulated via NKCC2 and the renal outer medullary K + channel ROMK1, across the apical cell membrane. These transport processes generate a lumen-positive transepithelial potential that drives additional paracellular reabsorption of Na + as well as the reabsorption of divalent cations, mainly Ca 2+ and Mg 2+ . Paracellular transport is regulated by the tight junction (TJ) in a size-, charge-, and water-selective manner. The main functional constituent of the TJ is the family of claudins with 27 members in mammals. Claudins consist of a four-transmembrane helix bundle, two extracellular segments that expand into the paracellular cleft, and intracellular N and C termini. Claudins interact in cis (within the same plasma membrane) and in trans (with claudins in the plasma membrane of neighbori...

show abstract

“…Furthermore, it fits well with the observation that the absence of cldn10b from the TAL led to decreased paracellular Na + permeability in mice (12).…”

Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 86%

See 1 more Smart Citation

Mosaic expression of claudins in thick ascending limbs of Henle results in spatial separation of paracellular Na ⁺ and Mg ²⁺ transport

Milatz

Himmerkus

Wulfmeyer

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

181

View full text Add to dashboard Cite

show abstract

“…Furosemide, by inhibiting the NKCC2 transporter in the TALH, induces natriuresis and diuresis, which in turn, abolished the transepithelial voltage for paracellular Mg ++ and Ca ++ reabsorption. 3,[28][29][30] The furosemide treatment significantly increased UV, FE Ca , and FE Mg ( Figure 3, C and D, Table 2). In addition to the elevated baseline levels, furosemide abolished the SAHA effects on plasma ( …”

Section: The Genetic and Cellular Origins Of Hdac Inhibitorinduced Hymentioning

confidence: 99%

Epigenetic Regulation of MicroRNAs Controlling CLDN14 Expression as a Mechanism for Renal Calcium Handling

Gong

Himmerkus

Plain

et al. 2015

Journal of the American Society of Nephrology

Self Cite

View full text Add to dashboard Cite

The kidney has a major role in extracellular calcium homeostasis. Multiple genetic linkage and association studies identified three tight junction genes from the kidney-claudin-14, -16, and -19-as critical for calcium imbalance diseases. Despite the compelling biologic evidence that the claudin-14/16/19 proteins form a regulated paracellular pathway for calcium reabsorption, approaches to regulate this transport pathway are largely unavailable, hindering the development of therapies to correct calcium transport abnormalities. Here, we report that treatment with histone deacetylase (HDAC) inhibitors downregulates renal CLDN14 mRNA and dramatically reduces urinary calcium excretion in mice. Furthermore, treatment of mice with HDAC inhibitors stimulated the transcription of renal microRNA-9 (miR-9) and miR-374 genes, which have been shown to repress the expression of claudin-14, the negative regulator of the paracellular pathway. With renal clearance and tubule perfusion techniques, we showed that HDAC inhibitors transiently increase the paracellular cation conductance in the thick ascending limb. Genetic ablation of claudin-14 or the use of a loop diuretic in mice abrogated HDAC inhibitor-induced hypocalciuria. The genetic mutations in the calcium-sensing receptor from patients with autosomal dominant hypocalcemia (ADH) repressed the transcription of miR-9 and miR-374 genes, and treatment with an HDAC inhibitor rescued the phenotypes of cell and animal models of ADH. Furthermore, systemic treatment of mice with antagomiRs against these miRs relieved claudin-14 gene silencing and caused an ADH-like phenotype. Together, our findings provide proof of concept for a novel therapeutic principle on the basis of epigenetic regulation of renal miRs to treat hypercalciuric diseases.

show abstract

“…Claudin-1 -/-Skin Barrier [207,208] Claudin-2 -/-Kidney, liver Barrier [209,210] Claudin-3 -/--- [211,212] Claudin-4 -/-Kidney Barrier [213] Claudin-5 -/-Blood-brain barrier Barrier [204] Claudin-7 -/-Intestine Adhesion [214] Claudin-10 -/-Kidney Na + adsorption [215] Claudin-11 -/-Inner ear Barrier [216] Claudin-14 -/-Kidney Regulation [217] Claudin-15 -/-Small intestine Mucosal differentiation [218] Claudin-16 -/-Kidney Barrier [219] Claudin-18 -/-Lung, bone Barrier Bone resorption and osteoclast differentiation [220,221] [222]…”

Section: Knockout Model Affected Organs Impaired Function Literaturementioning

confidence: 99%

Studies on cell junctions in an ex vivo human lung infection model

et al. 2015

View full text Add to dashboard Cite

Deletion of claudin-10 ( Cldn10 ) in the thick ascending limb impairs paracellular sodium permeability and leads to hypermagnesemia and nephrocalcinosis

Abstract: PHYSIOLOGYCorrection for "Deletion of claudin-10 (Cldn10) in the thick ascending limb impairs paracellular sodium permeability and leads to hypermagnesemia and nephrocalcinosis," by Tilman Breiderhoff, Nina Himmerkus, Marchel Stuiver, Kerim Mutig,

Cited by 134 publications

References 26 publications

Mosaic expression of claudins in thick ascending limbs of Henle results in spatial separation of paracellular Na ⁺ and Mg ²⁺ transport

Mosaic expression of claudins in thick ascending limbs of Henle results in spatial separation of paracellular Na ⁺ and Mg ²⁺ transport

Epigenetic Regulation of MicroRNAs Controlling CLDN14 Expression as a Mechanism for Renal Calcium Handling

Studies on cell junctions in an ex vivo human lung infection model

Contact Info

Product

Resources

About

Deletion of claudin-10 ( Cldn10 ) in the thick ascending limb impairs paracellular sodium permeability and leads to hypermagnesemia and nephrocalcinosis

Abstract: PHYSIOLOGYCorrection for "Deletion of claudin-10 (Cldn10) in the thick ascending limb impairs paracellular sodium permeability and leads to hypermagnesemia and nephrocalcinosis," by Tilman Breiderhoff, Nina Himmerkus, Marchel Stuiver, Kerim Mutig,

Cited by 134 publications

References 26 publications

Mosaic expression of claudins in thick ascending limbs of Henle results in spatial separation of paracellular Na + and Mg 2+ transport

Mosaic expression of claudins in thick ascending limbs of Henle results in spatial separation of paracellular Na + and Mg 2+ transport

Epigenetic Regulation of MicroRNAs Controlling CLDN14 Expression as a Mechanism for Renal Calcium Handling

Studies on cell junctions in an ex vivo human lung infection model

Contact Info

Product

Resources

About

Mosaic expression of claudins in thick ascending limbs of Henle results in spatial separation of paracellular Na ⁺ and Mg ²⁺ transport

Mosaic expression of claudins in thick ascending limbs of Henle results in spatial separation of paracellular Na ⁺ and Mg ²⁺ transport