Claudin-14 regulates renal Ca ++ transport in response to CaSR signalling via a novel microRNA pathway

Stuiver

et al. 2012

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137

155

mentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

Breiderhoff

Stuiver

et al. 2012

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137

155

“…Cldn14 is virtually absent from the TAL of mice under control conditions but is up-regulated in mice with a high dietary Ca 2+ intake (10,(20)(21)(22). This increase is accompanied by decreased Ca 2+ and Mg 2+ permeability in the TAL.…”

Section: Significancementioning

confidence: 86%

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

Milatz

Wulfmeyer

et al. 2016

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181

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...

“…Whether the kidney expresses ILDR1 has not been determined before. We first performed microdissection on mouse kidneys to isolate each nephron segment, including the glomerulus, the proximal tubule (PT), the thin limb (TL) and the thick limb (TAL) of the loop of Henle, the distal convoluted tubule (DCT), and the collecting duct (CD), obeying a rigorous anatomic criterion (14) (Fig. S1A).…”

Section: Resultsmentioning

confidence: 99%

ILDR1 is important for paracellular water transport and urine concentration mechanism

Gong

Sunq

et al. 2017

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Whether the tight junction is permeable to water remains highly controversial. Here, we provide evidence that the tricellular tight junction is important for paracellular water permeation and that Iglike domain containing receptor 1 (ILDR1) regulates its permeability. In the mouse kidney, ILDR1 is localized to tricellular tight junctions of the distal tubules. Genetic knockout of Ildr1 in the mouse kidney causes polyuria and polydipsia due to renal concentrating defects. Microperfusion of live renal distal tubules reveals that they are impermeable to water in normal animals but become highly permeable to water in Ildr1 knockout animals whereas paracellular ionic permeabilities in the Ildr1 knockout mouse renal tubules are not affected. Vasopressin cannot correct paracellular water loss in Ildr1 knockout animals despite normal effects on the transcellular aquaporin-2-dependent pathway. In cultured renal epithelial cells normally lacking the expression of Ildr1, overexpression of Ildr1 significantly reduces the paracellular water permeability. Together, our study provides a mechanism of how cells transport water and shows how such a mechanism may be exploited as a therapeutic approach to maintain water homeostasis.T ight junctions (TJs) are known to be leaky to ions and, thus, to constitute a paracellular pathway with ionic permselectivity similar to that of transmembrane channels (1). Whether the TJ is permeable to water, on the other hand, has been highly controversial. Jorge Fischbarg noticed that the corneal endothelium retained over 60% of water permeability even when AQP1, the only aquaporin expressed by these cells, was knocked out by genetic deletion (2). Rosenthal et al. have demonstrated that, in cultured renal epithelium expressing the claudin-2 protein, transepithelial water permeability was significantly higher than in cells without its expression (3). Using an optical microscopic approach, Spring and coworkers have directly measured the velocity of water flow across the tight junction and have ruled out the existence of any significant transjunctional water flow, at least for the bicellular TJ (bTJ) (4). The tricellular tight junction (tTJ) is a specialized cell junction different in ultrastructure from that of the bTJ (5). Unlike the bTJ, which is made of claudin and occludin (6), the proteins making the tTJ include tricellulin and angulins (LSR/angulin-1, ILDR1/angulin-2, and ILDR2/angulin-3) (7,8). Transgenic knockout (KO) of either tricellulin or Ildr1 in mice causes hearing loss due to degeneration of mechanosensory cochlear hair cells in the organ of Corti (9, 10). Peculiarly, neither the endocochlear potential nor the paracellular permeability in the stria vascularis changed in these mutant animals. The permeation property of tTJ therefore remains a major mystery.There are two forms of diabetes insipidus (DI): central (neurogenic) and nephrogenic. The nephrogenic DI (NDI) is caused by the inability of the kidney to reabsorb water. NDI is hereditary and has been linked to two genetic loci. The ...