The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway

Silvana Bazúa-Valenti, Lorena Rojas-Vega, María Castañeda-Bueno, Jonatan Barrera-Chimal, Rocío Bautista, Luz G. Cervantes-Pérez, Norma Vázquez, Consuelo Plata, Adrián R. Murillo-de-Ozores, Lorenza González-Mariscal, David Ellison, Daniela Riccardi, Norma A. Bobadilla, Gerardo Gamba

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Abstract

Background Hypercalciuria can result from activation of the basolateral calcium-sensing receptor (CaSR), which in the thick ascending limb of Henle’s loop controls Ca2+ excretion and NaCl reabsorption in response to extracellular Ca2+. However, the function of CaSR in the regulation of NaCl reabsorption in the distal convoluted tubule (DCT) is unknown. We hypothesized that CaSR in this location is involved in activating the thiazide-sensitive NaCl cotransporter (NCC) to prevent NaCl loss. Methods We used a combination of in vitro and in vivo models to examine the effects of CaSR on NCC activity. Because the KLHL3-WNK4-SPAK pathway is involved in regulating NaCl reabsorption in the DCT, we assessed the involvement of this pathway as well. Results Thiazide-sensitive 22Na+ uptake assays in Xenopus laevis oocytes revealed that NCC activity increased in a WNK4-dependent manner upon activation of CaSR with Gd3+. In HEK293 cells, treatment with the calcimimetic R-568 stimulated SPAK phosphorylation only in the presence of WNK4. The WNK4 inhibitor WNK463 also prevented this effect. Furthermore, CaSR activation in HEK293 cells led to phosphorylation of KLHL3 and WNK4 and increased WNK4 abundance and activity. Finally, acute oral administration of R-568 in mice led to the phosphorylation of NCC. Conclusions Activation of CaSR can increase NCC activity via the WNK4-SPAK pathway. It is possible that activation of CaSR by Ca2+ in the apical membrane of the DCT increases NaCl reabsorption by NCC, with the consequent, well known decrease of Ca2+ reabsorption, further promoting hypercalciuria.

Original languageEnglish (US)
Pages (from-to)1838-1848
Number of pages11
JournalJournal of the American Society of Nephrology
Volume29
Issue number7
DOIs
StatePublished - Jul 1 2018

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Calcium-Sensing Receptors
Kidney
N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine
Hypercalciuria
HEK293 Cells
Phosphorylation
Thiazides
Xenopus laevis
Oocytes
Oral Administration
Extremities
Membranes

ASJC Scopus subject areas

  • Nephrology

Cite this

Bazúa-Valenti, S., Rojas-Vega, L., Castañeda-Bueno, M., Barrera-Chimal, J., Bautista, R., Cervantes-Pérez, L. G., ... Gamba, G. (2018). The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway. Journal of the American Society of Nephrology, 29(7), 1838-1848. https://doi.org/10.1681/ASN.2017111155

The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway. / Bazúa-Valenti, Silvana; Rojas-Vega, Lorena; Castañeda-Bueno, María; Barrera-Chimal, Jonatan; Bautista, Rocío; Cervantes-Pérez, Luz G.; Vázquez, Norma; Plata, Consuelo; Murillo-de-Ozores, Adrián R.; González-Mariscal, Lorenza; Ellison, David; Riccardi, Daniela; Bobadilla, Norma A.; Gamba, Gerardo.

In: Journal of the American Society of Nephrology, Vol. 29, No. 7, 01.07.2018, p. 1838-1848.

Research output: Contribution to journalArticle

Bazúa-Valenti, S, Rojas-Vega, L, Castañeda-Bueno, M, Barrera-Chimal, J, Bautista, R, Cervantes-Pérez, LG, Vázquez, N, Plata, C, Murillo-de-Ozores, AR, González-Mariscal, L, Ellison, D, Riccardi, D, Bobadilla, NA & Gamba, G 2018, 'The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway', Journal of the American Society of Nephrology, vol. 29, no. 7, pp. 1838-1848. https://doi.org/10.1681/ASN.2017111155
Bazúa-Valenti S, Rojas-Vega L, Castañeda-Bueno M, Barrera-Chimal J, Bautista R, Cervantes-Pérez LG et al. The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway. Journal of the American Society of Nephrology. 2018 Jul 1;29(7):1838-1848. https://doi.org/10.1681/ASN.2017111155
Bazúa-Valenti, Silvana ; Rojas-Vega, Lorena ; Castañeda-Bueno, María ; Barrera-Chimal, Jonatan ; Bautista, Rocío ; Cervantes-Pérez, Luz G. ; Vázquez, Norma ; Plata, Consuelo ; Murillo-de-Ozores, Adrián R. ; González-Mariscal, Lorenza ; Ellison, David ; Riccardi, Daniela ; Bobadilla, Norma A. ; Gamba, Gerardo. / The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway. In: Journal of the American Society of Nephrology. 2018 ; Vol. 29, No. 7. pp. 1838-1848.
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abstract = "Background Hypercalciuria can result from activation of the basolateral calcium-sensing receptor (CaSR), which in the thick ascending limb of Henle’s loop controls Ca2+ excretion and NaCl reabsorption in response to extracellular Ca2+. However, the function of CaSR in the regulation of NaCl reabsorption in the distal convoluted tubule (DCT) is unknown. We hypothesized that CaSR in this location is involved in activating the thiazide-sensitive NaCl cotransporter (NCC) to prevent NaCl loss. Methods We used a combination of in vitro and in vivo models to examine the effects of CaSR on NCC activity. Because the KLHL3-WNK4-SPAK pathway is involved in regulating NaCl reabsorption in the DCT, we assessed the involvement of this pathway as well. Results Thiazide-sensitive 22Na+ uptake assays in Xenopus laevis oocytes revealed that NCC activity increased in a WNK4-dependent manner upon activation of CaSR with Gd3+. In HEK293 cells, treatment with the calcimimetic R-568 stimulated SPAK phosphorylation only in the presence of WNK4. The WNK4 inhibitor WNK463 also prevented this effect. Furthermore, CaSR activation in HEK293 cells led to phosphorylation of KLHL3 and WNK4 and increased WNK4 abundance and activity. Finally, acute oral administration of R-568 in mice led to the phosphorylation of NCC. Conclusions Activation of CaSR can increase NCC activity via the WNK4-SPAK pathway. It is possible that activation of CaSR by Ca2+ in the apical membrane of the DCT increases NaCl reabsorption by NCC, with the consequent, well known decrease of Ca2+ reabsorption, further promoting hypercalciuria.",
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T1 - The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway

AU - Bazúa-Valenti, Silvana

AU - Rojas-Vega, Lorena

AU - Castañeda-Bueno, María

AU - Barrera-Chimal, Jonatan

AU - Bautista, Rocío

AU - Cervantes-Pérez, Luz G.

AU - Vázquez, Norma

AU - Plata, Consuelo

AU - Murillo-de-Ozores, Adrián R.

AU - González-Mariscal, Lorenza

AU - Ellison, David

AU - Riccardi, Daniela

AU - Bobadilla, Norma A.

AU - Gamba, Gerardo

PY - 2018/7/1

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N2 - Background Hypercalciuria can result from activation of the basolateral calcium-sensing receptor (CaSR), which in the thick ascending limb of Henle’s loop controls Ca2+ excretion and NaCl reabsorption in response to extracellular Ca2+. However, the function of CaSR in the regulation of NaCl reabsorption in the distal convoluted tubule (DCT) is unknown. We hypothesized that CaSR in this location is involved in activating the thiazide-sensitive NaCl cotransporter (NCC) to prevent NaCl loss. Methods We used a combination of in vitro and in vivo models to examine the effects of CaSR on NCC activity. Because the KLHL3-WNK4-SPAK pathway is involved in regulating NaCl reabsorption in the DCT, we assessed the involvement of this pathway as well. Results Thiazide-sensitive 22Na+ uptake assays in Xenopus laevis oocytes revealed that NCC activity increased in a WNK4-dependent manner upon activation of CaSR with Gd3+. In HEK293 cells, treatment with the calcimimetic R-568 stimulated SPAK phosphorylation only in the presence of WNK4. The WNK4 inhibitor WNK463 also prevented this effect. Furthermore, CaSR activation in HEK293 cells led to phosphorylation of KLHL3 and WNK4 and increased WNK4 abundance and activity. Finally, acute oral administration of R-568 in mice led to the phosphorylation of NCC. Conclusions Activation of CaSR can increase NCC activity via the WNK4-SPAK pathway. It is possible that activation of CaSR by Ca2+ in the apical membrane of the DCT increases NaCl reabsorption by NCC, with the consequent, well known decrease of Ca2+ reabsorption, further promoting hypercalciuria.

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