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

Journal of the American Society of Nephrology : JASN
Silvana Bazúa-ValentiGerardo Gamba

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 administrat...Continue Reading

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Citations

Aug 9, 2018·American Journal of Physiology. Renal Physiology·Mauricio Ostrosky-FridGerardo Gamba
Dec 4, 2019·Physiological Reviews·Ewout J HoornRobert A Fenton
Jul 15, 2020·Cells·Daria S OstroverkhovaKerim Mutig
Sep 10, 2019·Physiological Reports·Mohammed Z FerdausAndrew S Terker
Aug 1, 2020·International Journal of Molecular Sciences·Osamu YamazakiShigeru Shibata
Nov 3, 2020·American Journal of Physiology. Renal Physiology·Yujiro Maeoka, James A McCormick
Nov 25, 2020·Pediatric Nephrology : Journal of the International Pediatric Nephrology Association·Michael FreundlichBernardo Rodriguez-Iturbe
Jan 26, 2021·American Journal of Physiology. Renal Physiology·Adrián Rafael Murillo-de-OzoresMaría Castañeda-Bueno

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