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Review
. 2023 Sep 1;32(5):451-457.
doi: 10.1097/MNH.0000000000000915. Epub 2023 Jul 7.

Regulation of the WNK4-SPAK-NCC pathway by the calcium-sensing receptor

María Chávez-Canales  1 , Janeth Alejandra García  2 , Gerardo Gamba  2
Affiliations
Review

Regulation of the WNK4-SPAK-NCC pathway by the calcium-sensing receptor

María Chávez-Canales et al. Curr Opin Nephrol Hypertens. .

Abstract

Purpose of review: Regulation of the sodium chloride cotransporter (NCC) in the distal convoluted tubule (DCT) plays a crucial role in renal salt handling. The calcium-sensing receptor (CaSR) has been shown to activate NCC through the WNK4-SPAK pathway, which is independent of the Renin-Angiotensin-Aldosterone system. In this review, we examine new information about the mechanism of how the CaSR regulates NCC through the WNK4-SPAK pathway and its physiological and therapeutic implications.

Recent findings: The activation of CaSR in TALH cells during hypercalcemia inhibits NKCC2 and ROMK activity, reducing paracellular Ca2+ reabsorption but decreasing salt reabsorption. This pathway enables NaCl reabsorption in the DCT while promoting Ca2+ excretion. CaSR activation in the apical DCT stimulates a signaling pathway involving PKC, WNK4, and SPAK, which increases NCC activation to recover the NaCl not reabsorbed in TAHL. Glucose or fructose acting as calcimimetics enhance apical CaSR sensitivity, increasing NCC activity, which contribute to the mechanism of hypertension prevalence in diabetic patients or in those with high fructose consumption.

Summary: These findings reveal the importance of the CaSR-mediated activation of the WNK4-SPAK pathway in regulating salt and calcium homeostasis and its potential as a therapeutic target for hypertension and related diseases.

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References

    1. Gamba G. The evolving field of salt transport regulation in the Steve Hebert Lecture. Am J Physiol Renal Physiol 2016; 311:F68–F70.
    1. Gamba G. Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters. Physiol Rev 2005; 85:423–493.
    1. Lifton RP, Gharavi AG, Geller DS. Molecular mechanisms of human hypertension. Cell 2001; 104:545–556.
    1. Simon DB, Nelson-Williams C, Johnson-Bia M, et al. Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nature Genetics 1996; 12:24–30.
    1. Simon DB, Lifton RP. The molecular basis of inherited hypokalemic alkalosis: Bartter's and Gitelman's syndromes. Am J Physiol 1996; 271 (5 Pt 2):F961–F966.

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