Ca2+, Mg2+ and K+ transport in the cortical and medullary thick ascending limb of the rat nephron: influence of transepithelial voltage

Mandon, B.; Siga, Esteban; Roinel, N.; Rouffignac, C. de

doi:10.1007/bf00374924

Cited by 60 publications

(46 citation statements)

References 10 publications

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“…A number of elegant in vitro studies using perfused TAL tubules have examined the relationship between the flux of Mg 2+ and the transepithelial voltage (V t ) (Di Stefano et al, 1993;Hebert and Andreoli, 1986;Mandon et al, 1993;Shareghi and Agus, 1982 reabsorption on transepithelial voltage suggests a passive process via the paracellular pathway. When TAL is perfused with isotonic NaCl solutions, the lumen voltage is positive at 3-10 mV owing to apical membrane K + secretion (Greger and Schlatter, 1983).…”

Section: Discussionmentioning

confidence: 99%

Paracellin-1 and the modulation of ion selectivity of tight junctions

Hou

Paul

Goodenough

2005

Journal of Cell Science

214

268

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Tight junctions play a key selectivity role in the paracellular conductance of ions. Paracellin-1 is a member of the tight junction claudin protein family and mutations in the paracellin-1 gene cause a human hereditary disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) with severe renal Mg2+ wasting. The mechanism of paracellin-1 function and its role in FHHNC are not known. Here, we report that in LLC-PK1 epithelial cells paracellin-1 modulated the ion selectivity of the tight junction by selectively and significantly increasing the permeability of Na+ (with no effects on Cl-) and generated a high permeability ratio of Na+ to Cl-. Mutagenesis studies identified a locus of amino acids in paracellin-1 critical for this function. Mg2+ flux across cell monolayers showed a far less-pronounced change (compared to monovalent alkali cations) following exogenous protein expression, suggesting that paracellin-1 did not form Mg2+-selective paracellular channels. We hypothesize that in the thick ascending limb of the nephron, paracellin-1 dysfunction, with a concomitant loss of cation selectivity, could contribute to the dissipation of the lumen-positive potential that is the driving force for the reabsorption of Mg2+.

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Section: Discussionmentioning

confidence: 99%

Paracellin-1 and the modulation of ion selectivity of tight junctions

Hou

Paul

Goodenough

2005

Journal of Cell Science

214

268

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“…The reabsorption of Mg 2ϩ in TAL is a passive process via the paracellular pathway and highly dependent on the transepithelial potential as a driving force (35)(36)(37). When TAL is perfused with isotonic NaCl solutions, the lumen voltage is positive at 3-10 mV (Vte) owing to apical membrane K ϩ secretion (38).…”

Section: Discussionmentioning

confidence: 99%

Transgenic RNAi Depletion of Claudin-16 and the Renal Handling of Magnesium

Hou

Shan

Wang

et al. 2007

Journal of Biological Chemistry

143

166

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Tight junctions play a key role in mediating paracellular ion reabsorption in the kidney. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a human disorder caused by mutations in the tight junction protein claudin-16. However, the molecular mechanisms underlining the renal handling of magnesium and its dysfunction causing FHHNC are unknown. Here we show that claudin-16 plays a key role in maintaining the paracellular cation selectivity of the thick ascending limbs of the nephron. Using RNA interference, we have generated claudin-16-deficient mouse models. Claudin-16 knock-down (KD) mice exhibit chronic renal wasting of magnesium and calcium and develop renal nephrocalcinosis. Our data suggest that claudin-16 forms a non-selective paracellular cation channel, rather than a selective Mg 2؉ /Ca 2؉ channel as previously proposed. Our study highlights the pivotal importance of the tight junction in renal control of ion homeostasis and provides answer to the pathogenesis of FHHNC. We anticipate our study to be a starting point for more sophisticated in vivo analysis of tight junction proteins in renal functions. Furthermore, tight junction proteins could be major targets of drug development for electrolyte disorders.The human renal disorder, familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC, 3 OMIM 248250), is characterized by progressive renal Mg 2ϩ and Ca 2ϩ wasting, leading to impaired renal function and chronic renal failure. FHHNC is genetically linked to mutations in the gene of claudin-16 (CLDN16, also known as paracellin-1; Ref. 1), which is expressed exclusively in the kidney (2). The claudins comprise a 22 gene family that encodes essential structural components of the tight junction, the principal regulator of paracellular permeability. In vitro studies have shown that ion selectivity of the paracellular conductance (see review: Ref.3) is a complex function of claudin subtype and cellular context (4, 5). Thus, in vivo models of FNNHC are essential to our understanding of its pathogenesis.To develop an in vivo model of FNNHC, we have employed transgenic RNA interference (RNAi), which is in theory more rapid and flexible than a conventional knock-out approach. While the use of transgenic RNAi has been limited thus far, it has been shown that an RNAi knockdown of Rasa1 recapitulates a null phenotype in mice (6). In addition, transgenic RNAi has been used to establish a role for Ryk in axon guidance (7) and a role for Nramp1 in controlling susceptibility to Type 1 diabetes (8). We used lentiviral transgenesis because it is more resistant than onco-retroviral transgenesis to epigenetic silencing during embryonic development (9 -11).In this study, we report the generation of CLDN16-deficient transgenic mouse lines using RNAi and have established physiological functions of CLDN16. We observed homeostatic changes of Mg 2ϩ , Ca 2ϩ , Na ϩ , and K ϩ resulting from RNAimediated knockdown. The lumen-positive transepithelial potential in the thick ascending limb (TAL) of ...

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“…It was reported (Suki et al 1980) that the mTAL possesses passive potential-dependent net Ca 2+ reabsorption. However, it was also reported (Mandon et al 1993) that the mTAL of rat kidney can reabsorb neither Mg 2+ nor Ca 2+ , whatever transepithelial voltage (Vte). Further studies are mandatory to evaluate whether the effects of the CaSR activation is related to the net Ca 2+ reabsorption in the mTALs due to the limitation of the information and arguments regarding the presence of transepithelial Ca 2+ transport in the mTALs.…”

Section: Contribution Of the Casr To Transepithelial Ca 2+ Transport mentioning

confidence: 97%

Chloride-Dependent Intracellular pH Regulation via Extracellular Calcium-Sensing Receptor in the Medullary Thick Ascending Limb of the Mouse Kidney

Aslanova

Morimoto

Farajov

et al. 2006

Tohoku J. Exp. Med.

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The extracellular calcium-sensing receptor (CaSR) located in either luminal or basolateral cell membranes of various types of renal tubules including proximal tubules, Henle's loop and collecting ducts has been thought to play a fundamental role in electrolyte metabolism. To further identify the physiological roles of the CaSR, we examined the effects of Ca 2+ and calcimimetics neomycin (Neo), gentamicin and gadolinium chloride (Gd 3+ ) on the intracellular pH (pHi) of in vitro microperfused mouse medullary thick ascending limb (mTAL) cells of Henle's loop, by loading the cells with fluorescent pH indicator 2′,7′-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein and measuring the ratio of fluorescence emission at 530 nm after exciting the dye at 490 and 440 nm. In a steady-state condition in Hepes-buffered solution, the pHi in the mTALs was 7.29 ± 0.04 (n = 9). A concentration of 200 μ mol/l Neo in the basolateral side decreased the pHi after 1 min by −0.13 ± 0.02 (n = 34, p < 0.0001). The other calcimimetics showed similar effects on pHi, whereas none of these calcimimetics in the lumen affected pHi. Na + removal or the inhibition of Na + and proton transport with amiloride, bumetanide, or bafilomycin did not eliminate the effect of Neo on pHi. On the other hand, Cl − removal clearly eliminated the Neo-induced pHi decrease (−0.06 ± 0.01 vs −0.00 ± 0.05 in Cl − removal, n = 4, p < 0.003). Thus, we have demonstrated for the first time that the CaSR is involved in the regulation of the pHi in the mTAL and requires Cl − to exert its effect. intracellular pH; renal medulla; chloride; amiloride; BCECF

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Ca2+, Mg2+ and K+ transport in the cortical and medullary thick ascending limb of the rat nephron: influence of transepithelial voltage

Cited by 60 publications

References 10 publications

Paracellin-1 and the modulation of ion selectivity of tight junctions

Paracellin-1 and the modulation of ion selectivity of tight junctions

Transgenic RNAi Depletion of Claudin-16 and the Renal Handling of Magnesium

Chloride-Dependent Intracellular pH Regulation via Extracellular Calcium-Sensing Receptor in the Medullary Thick Ascending Limb of the Mouse Kidney

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