Effect of thiazide on renal gene expression of apical calcium channels and calbindins

Lee, Chien Te; Shang, Shuhua; Lai, Li Wen; Yong, Kim Chong; Lien, Yeong‐Hau H.

doi:10.1152/ajprenal.00437.2003

Cited by 54 publications

(49 citation statements)

References 44 publications

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“…Second, when Pvalb Ϫ/Ϫ mice are salt-repleted, their urinary calcium/creatine ratio remains lower (Ϸ0.75) than in wildtype mice (Ϸ1.3). These results indicate that thiazide-induced hypocalciuria may occur without extracellular volume contraction, consistent with a mouse model of chronic treatment with lower doses of thiazide (22). Several models with enhanced PT-passive Ca 2ϩ reabsorption are characterized by profound structural damage of the DCT and/or a reduced expression of molecules involved in the distal Ca 2ϩ transport (20,21,23).…”

Section: Discussionsupporting

confidence: 82%

Renal expression of parvalbumin is critical for NaCl handling and response to diuretics

Belge¹,

Gailly²,

Schwaller

et al. 2007

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

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The distal convoluted tubule (DCT) plays an essential role in the reabsorption of NaCl by the kidney, a process that can be inhibited by thiazide diuretics. Parvalbumin (PV), a Ca 2؉ -binding protein that plays a role in muscle fibers and neurons, is selectively expressed in the DCT, where its role remains unknown. We therefore investigated the renal phenotype of PV knockout mice (Pvalb ؊/؊ ) vs. wild-type (Pvalb ؉/؉ ) littermates. PV colocalized with the thiazidesensitive Na ؉ -Cl ؊ cotransporter (NCC) in the early DCT. The Pvalb ؊/؊ mice showed increased diuresis and kaliuresis at baseline with higher aldosterone levels and lower lithium clearance. Acute furosemide administration increased diuresis and natriuresis/kaliuresis, but, surprisingly, did not increase calciuria in Pvalb ؊/؊ mice. NaCl supplementation of Pvalb ؊/؊ mice increased calciuria at baseline and after furosemide. The Pvalb ؊/؊ mice showed no significant diuretic response to hydrochlorothiazide, but an accentuated hypocalciuria. A decreased expression of NCC was detected in the early DCT of Pvalb ؊/؊ kidneys in the absence of ultrastructural and apoptotic changes. The PV-deficient mice had a positive Ca 2؉ balance and increased bone mineral density. Studies in mouse DCT cells showed that endogenous NCC expression is Ca 2؉ -dependent and can be modulated by the levels of PV expression. These results suggest that PV regulates the expression of NCC by modulating intracellular Ca 2؉ signaling in response to ATP in DCT cells. They also provide insights into the Ca 2؉ -sparing action of thiazides and the pathophysiology of distal tubulopathies.distal convoluted tubule ͉ kidney ͉ salt-losing nephropathy ͉ sodium-chloride cotransport P arvalbumin (PV) belongs to the superfamily of EF-hand Ca 2ϩ -binding proteins that play a role in multiple cellular processes, including gene transcription, ion transport, protein phosphorylation, and enzymatic activities (1). These proteins possess well conserved helix-loop-helix motifs that bind Ca 2ϩ ions with high affinity, leading to conformational changes. The conformational plasticity and the cell-specific expression of these Ca 2ϩ sensor or buffer proteins contribute to the versatility of Ca 2ϩ signaling (2). PV is a 109-aa cytosolic protein that contains a pair of functional EF-hand motifs forming a stable unit that binds two Ca 2ϩ ions (3). This Ca 2ϩ buffer is expressed in a restricted number of vertebrate tissues, including fast-contracting/relaxing skeletal muscle fibers and GABA neurons in the brain (4). The generation of PV knockout (Pvalb Ϫ/Ϫ ) mice confirmed the important role played by PV in muscle and brain (5). The fast muscles of Pvalb Ϫ/Ϫ mice exhibit a decreased relaxation rate of the twitch (5), suggesting that PV facilitates Ca 2ϩ diffusion from myofibrils to the sarcoplasmic reticulum (6). The lack of PV in the brain induces changes in short-term synaptic plasticity and modified network properties, resulting in increased susceptibility to epileptic seizures (7). Although no human disease is ass...

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Section: Discussionsupporting

confidence: 82%

Renal expression of parvalbumin is critical for NaCl handling and response to diuretics

Belge¹,

Gailly²,

Schwaller

et al. 2007

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

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“…A similar compensatory mechanism has been reported in the gentamicin-and diabetes-induced hypercalciuria by our group (14,16). Thiazides induce hypocalciuria via different mechanisms depending on the volume status: with volume depletion, increased passive reabsorption in PT is the key mechanism (18); without volume depletion, the increased Ca reabsorption mainly occurs in the DCT via upregulation of TRPV5/6 and CBD-28k (13).…”

supporting

confidence: 62%

The role of calbindin-D28k on renal calcium and magnesium handling during treatment with loop and thiazide diuretics

Lee

et al. 2016

American Journal of Physiology-Renal Physiology

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Lee C, Ng H, Lee Y, Lai L, Lien YH. The role of calbindinD28k on renal calcium and magnesium handling during treatment with loop and thiazide diuretics. Am J Physiol Renal Physiol 310: F230 -F236, 2016. First published November 18, 2015 doi:10.1152/ajprenal.00057.2015) is a calcium binding protein located in the distal convoluted tubule (DCT) and plays an important role in active calcium transport in the kidney. Loop and thiazide diuretics affect renal Ca and Mg handling: both cause Mg wasting, but have opposite effects on Ca excretion as loop diuretics increase, but thiazides decrease, Ca excretion. To understand the role of CBD-28k in renal Ca and Mg handling in response to diuretics treatment, we investigated renal Ca and Mg excretion and gene expression of DCT Ca and Mg transport molecules in wild-type (WT) and CBD-28k knockout (KO) mice. Mice were treated with chlorothiazide (CTZ; 50 mg·kg Ϫ1 ·day Ϫ1 ) or furosemide (FSM; 30 mg·kg Ϫ1 ·day Ϫ1 ) for 3 days. To avoid volume depletion, salt was supplemented in the drinking water. Urine Ca excretion was reduced in WT, but not in KO mice, by CTZ. FSM induced similar hypercalciuria in both groups. DCT Ca transport molecules, including transient receptor potential vanilloid 5 (TRPV5), TRPV6, and CBD-9k, were upregulated by CTZ and FSM in WT, but not in KO mice. Urine Mg excretion was increased and transient receptor potential subfamily M, member 6 (TRPM6) was upregulated by both CTZ and FSM in WT and KO mice. In conclusion, CBD-28k plays an important role in gene expression of DCT Ca, but not Mg, transport molecules, which may be related to its being a Ca, but not a Mg, intracellular sensor. The lack of upregulation of DCT Ca transport molecules by thiazides in the KO mice indicates that the DCT Ca transport system is critical for Ca conservation by thiazides.furosemide; thiazides; TRPV5; TRPV6; TRPM6; calbindin-D28k; calbindin-D9k LOOP AND THIAZIDE DIURETICS are commonly used for treating hypertension, congestive heart failure, and other disorders with fluid overload (21). Loop diuretics are inhibitors of the Na-K2Cl cotransporter (NKCC) in the thick ascending limb of the loop of Henle (TALH), while thiazides inhibit the Na-Cl cotransporter (NCC) in the distal convoluted tubule (DCT). Both cause renal loss of Na, K, and Mg, but have different effects on renal Ca handling: loop diuretics cause hypercalciuria, while thiazides cause hypocalciuria (6,19). Those distinct effects on Ca excretion are also observed in patients with mutations in the NKCC (Barter syndrome) and NCC (Gitelman syndrome), respectively (22).In the kidney, Ca is reabsorbed through passive paracellular transport in the proximal tubule (PT) and TALH and active transcellular transport in the DCT (3). The gatekeeper of this active Ca transport mechanism is TRPV5. Ca enters cells across the apical TRPV5, then binds to calbindin-D28k (CBD28k), the major intracellular calcium binding proteins in DCT, and diffuses to the basolateral membrane, where Ca is extruded via the Na/Ca exchanger or Ca pumps (5)....

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“…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. These data suggest that increased distal nephron Ca reabsorption may be an important mechanism for TZinduced hypocalciuria in some circumstances (17,23).We set out to determine the mechanism by which chronic TZ administration leads to decreased urine Ca excretion in human stone formers with IH; if increased proximal tubule sodium and Ca reabsorption is at least some component of this phenomenon, then in addition to lowering the recurrence of stones, decreased Randall's plaque formation could be a second benefit of TZ treatment. …”

mentioning

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).…”

mentioning

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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Effect of thiazide on renal gene expression of apical calcium channels and calbindins

Cited by 54 publications

References 44 publications

Renal expression of parvalbumin is critical for NaCl handling and response to diuretics

Renal expression of parvalbumin is critical for NaCl handling and response to diuretics

The role of calbindin-D28k on renal calcium and magnesium handling during treatment with loop and thiazide diuretics

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

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