Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia

Nijenhuis, Tom; Vallon, Volker; Kemp, Annemiete W.C.M. van der; Loffing, Johannes; Hoenderop, Joost G. J.; Bindels, René J. M.

doi:10.1172/jci24134

Cited by 426 publications

(354 citation statements)

References 49 publications

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“…Hence, the NCC abundance in uEV was analyzed in these patients following treatment with thiazide diuretics, the main anti-hypertensive drug. In line with several studies in animal models [72,73], NCC abundance was increased after thiazide treatment [70]. Furthermore, pre-treatment abundance of NCC in uEVs correlated with blood pressure response to thiazide diuretics, which implies that this method could be used to predict patients’ thiazide sensitivity.…”

Section: The Role Of Nccsv In (Patho)physiologysupporting

confidence: 81%

Role of the alternative splice variant of NCC in blood pressure control

2018

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The renal thiazide-sensitive sodium-chloride cotransporter (NCC), located in the distal convoluted tubule (DCT) of the kidney, plays an important role in blood pressure regulation by fine-tuning sodium excretion. The human SLC12A3 gene, encoding NCC, gives rise to three isoforms, of which only the third isoform (NCC3) has been extensively investigated so far. However, recent studies unraveled the importance of the isoforms 1 and 2, collectively referred to as NCC splice variant (NCCSV), in several (patho)physiological conditions. In the human kidney, NCCSV localizes to the apical membrane of the DCT and could constitute a functional route for renal sodium-chloride reabsorption. Analysis of urinary extracellular vesicles (uEVs), a non-invasive method for measuring renal responses, demonstrated that NCCSV abundance changes in response to acute water loading and correlates with patients’ thiazide responsiveness. Furthermore, a novel phosphorylation site at serine 811 (S811), exclusively present in NCCSV, was shown to play an instrumental role in NCCSV as well as NCC3 function. This review aims to summarize these new insights of NCCSV function in humans that broadens the understanding on NCC regulation in blood pressure control.

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Section: The Role Of Nccsv In (Patho)physiologysupporting

confidence: 81%

Role of the alternative splice variant of NCC in blood pressure control

2018

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“…This could reflect decreased reabsorption in either the thick ascending limb or in the distal nephron. Nijenhuis et al (28) found that mice exposed to TZ had a decrease in the expression of the magnesium channel TRPM6 in the distal tubule. This could be one potential explanation for the relative decrease in magnesium reabsorption seen in our subjects.…”

Section: F595 Thiazide Increases Proximal Tubule Calcium Reabsorptionmentioning

confidence: 99%

“…However, these studies have rarely included subjects with IH and usually were limited to a week or less in duration. Studies in animals suggest that increased proximal tubule sodium and Ca absorption is a likely mechanism for TZ hypocalciuria (28), but not necessarily the only one (23). Rodents exposed to TZ exhibit upregulation of the sodium-hydrogen exchanger, the sodiumchloride cotransporter, and several isoforms of the epithelial sodium channel (ENaC) (25), and lithium (Li) clearance data indicate that proximal Na reabsorption increases with shortterm TZ administration (28).…”

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confidence: 99%

“…Studies in animals suggest that increased proximal tubule sodium and Ca absorption is a likely mechanism for TZ hypocalciuria (28), but not necessarily the only one (23). Rodents exposed to TZ exhibit upregulation of the sodium-hydrogen exchanger, the sodiumchloride cotransporter, and several isoforms of the epithelial sodium channel (ENaC) (25), and lithium (Li) clearance data indicate that proximal Na reabsorption increases with shortterm TZ administration (28). However, TZ can prevent (23) or significantly blunt (17) the rise in Ca excretion seen when rodents receive sodium supplementation to prevent volume depletion during TZ administration, and upregulation of distal tubule Ca channel (TRPV5) and calbindin expression has been reported with administration of TZ in some (17,23), but not all (27), studies.…”

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confidence: 99%

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Role of proximal tubule in the hypocalciuric response to thiazide of patients with idiopathic hypercalciuria

Bergsland

Worcester

Coe

2013

American Journal of Physiology-Renal Physiology

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Bergsland KJ, Worcester EM, Coe FL. Role of proximal tubule in the hypocalciuric response to thiazide of patients with idiopathic hypercalciuria. Am J Physiol Renal Physiol 305: F592-F599, 2013. First published May 29, 2013 doi:10.1152/ajprenal.00116.2013The most common metabolic abnormality found in calcium (Ca) kidney stone formers is idiopathic hypercalciuria (IH). Using endogenous lithium (Li) clearance, we previously showed that in IH, there is decreased proximal tubule sodium absorption, and increased delivery of Ca into the distal nephron. Distal Ca reabsorption may facilitate the formation of Randall's plaque (RP) by washdown of excess Ca through the vasa recta toward the papillary tip. Elevated Ca excretion leads to increased urinary supersaturation (SS) with respect to calcium oxalate (CaOx) and calcium phosphate (CaP), providing the driving force for stone growth on RP. Thiazide (TZ) diuretics reduce Ca excretion and prevent stone recurrence, but the mechanism in humans is unknown. We studied the effect of chronic TZ administration on renal mineral handling in four male IH patients using a fixed three meal day in the General Clinical Research Center. Each subject was studied twice: once before treatment and once after 4 -7 mo of daily chlorthalidone treatment. As expected, urine Ca fell with TZ, along with fraction of filtered Ca excreted. Fraction of filtered Li excreted also fell sharply with TZ, as did distal delivery of Ca. Unexpectedly, TZ lowered urine pH. Together with reduced urine Ca, this led to a marked fall in CaP SS, but not CaOx SS. Since CaOx stone formation begins with an initial CaP overlay on RP, by lowering urine pH and decreasing distal nephron Ca delivery, TZ might diminish stone risk both by reducing CaP SS, as well as slowing progression of RP. calcium oxalate; calcium phosphate; idiopathic hypercalciuria; kidney calculi; thiazide THE MOST COMMON METABOLIC abnormality found in calcium (Ca) stone formers is so-called idiopathic hypercalciuria (IH) (40). Patients with IH absorb more Ca from a given meal than normal people (N), but also have abnormally decreased renal tubule Ca reabsorption, so that they often excrete more Ca than they have absorbed, exhibit decreased bone density, and have a propensity for increased fractures (22,42). Elevated urine Ca excretion leads to increased urinary supersaturation (SS) with respect to both calcium oxalate (CaOx) and calcium phosphate (CaP), providing the driving force for kidney stone formation (36). In addition, urine Ca excretion is correlated with the amount of interstitial apatite deposits (called Randall's plaque) found on the surface of the renal papillae (19). These deposits are the attachment sites for most CaOx stones and appear to be critical for stone formation (14). A plausible mechanism by which increased Ca reaches the deep papillae is via washdown from reabsorption in the thick ascending limb; an increase in delivery of Ca to this site would tend to increase reabsorption and washdown into the papilla and potentially increase...

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“…Elles sont également impliquées dans la réabsorp-tion active du Ca 2+ [3]. Par ailleurs, la contraction volémique stimule la réabsorption de Na + dans le tube proximal, ainsi qu'une réabsorption paracellulaire de Ca 2+ pouvant rendre compte de l'hypocalciurie typiquement associée au syndrome de Gitelman ou à la prise de diurétiques thiazidiques [4]. Des travaux récents ont permis de mieux comprendre les méca-nismes de transport opérant au niveau du TCD, y compris le rôle inattendu de la parvalbumine -un tampon calcique spécifiquement exprimé dans ce segment du néphron.…”

Section: Cotransporteur Ncc Et Syndrome De Gitelmanunclassified

Parvalbumine et régulation du transport ionique dans le tube contourné distal du rein

Belge

Devuyst

2010

Med Sci (Paris)

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> Chaque jour, nos reins filtrent environ 180 litres de plasma et réabsorbent plus de 99 % du sodium filtré, ce qui correspond à plus d'un kilogramme de sel (NaCl). Cette réabsorption massive de NaCl dépend de mécanismes opérant dans les cellules épithéliales bordant divers segments tubulaires spécialisés au niveau du néphron [1]. Ainsi, les cellules du tube proximal du rein réabsorbent les deux tiers environ de la charge filtrée, alors que les segments plus distaux du néphron -portion épaisse ascendante de l'anse de Henle (TAL, thick ascending limb) et tube contourné distal (TCD) -sont responsables de la réabsorption de 25 % et de 5 à 10 % du NaCl filtré, respectivement. La réabsorption de NaCl dans ces deux segments peut être inhibée par des agents diurétiques. Les diurétiques agissant au niveau de l'anse (furosémide, bumétanide), qui bloquent le cotransporteur Na + -K + -2Cl -(NKCC2) au niveau du TAL, sont de puissants agents utilisés pour traiter la rétention hydrosaline, alors que les dérivés thiazidiques (hydrochlorothiazide, bendrofluméthiazide, indapamide…), qui bloquent le cotransporteur Na + -Cl -(NCC) au niveau du TCD, sont largement utilisés dans le traitement de l'hypertension artérielle (Figure 1). Cotransporteur NCC et syndrome de GitelmanOutre le cotransporteur NCC sensible aux thiazides, les cellules de la portion initiale du TCD possèdent un canal chlorure ClC-Kb associé à une sous-unité (barttine) au pôle basolatéral. Elles sont également impliquées dans la réabsorp-tion active du Ca 2+ et du Mg 2+ via les canaux apicaux TRPV5 (Transient receptor potential cation channel subfamily V member 5) et TRPM6, respectivement. La diffusion cytosolique des cations divalents se fait par liaison aux tampons calbindines (CB-D28k et CB-D9k) et l'expulsion basolatérale via une Ca 2+ -ATPase et un échangeur Na + -Ca 2+ (NCX1). Les mécanismes de transport opérant dans le TCD sont perturbés dans le syndrome de Gitelman, une maladie autosomique récessive (prévalence 1/50 000) qui associe déplétion sodée, hypokaliémie, alcalose métabolique, hypomagnésémie et hypocalciurie. Le syndrome de Gitelman est causé par des mutations invalidantes du gène SLC12A3 codant pour le cotransporteur apical NCC [2]. L'inactivation de NCC induit une perte de sel et une contraction volémique, stimulant l'axe rénine-angiotensine-aldostérone et entraînant une réabsorption électro-génique de Na + dans le canal collecteur via le canal épithélial sodique ENaC. Ce dernier processus stimule la sécrétion distale des cations K + et H + , induisant une hypokaliémie et une alcalose méta-bolique [3]. Par ailleurs, la contraction volémique stimule la réabsorption de Na + dans le tube proximal, ainsi qu'une réabsorption paracellulaire de Ca 2+ pouvant rendre compte de l'hypocalciurie typiquement associée au syndrome de Gitelman ou à la prise de diurétiques thiazidiques [4]. Des travaux récents ont permis de mieux comprendre les méca-nismes de transport opérant au niveau du TCD, y compris le rôle inattendu de la parvalbumine -un tampon calcique spé...

show abstract

Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia

Cited by 426 publications

References 49 publications

Role of the alternative splice variant of NCC in blood pressure control

Role of the alternative splice variant of NCC in blood pressure control

Role of proximal tubule in the hypocalciuric response to thiazide of patients with idiopathic hypercalciuria

Parvalbumine et régulation du transport ionique dans le tube contourné distal du rein

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