Abstract
The kidney is essential for systemic calcium homeostasis. Urinary calcium excretion can be viewed as an integrative renal response to endocrine and local stimuli. The extracellular calcium-sensing receptor (CaSR) elicits a number of adaptive reactions to increased plasma Ca2+ levels including the control of parathyroid hormone release and regulation of the renal calcium handling. Calcium reabsorption in the distal nephron of the kidney is functionally coupled to sodium transport. Apart from Ca2+ transport systems, CaSR signaling affects relevant distal Na+-(K+)-2Cl− cotransporters, NKCC2 and NCC. NKCC2 and NCC are activated by a kinase cascade comprising with-no-lysine [K] kinases (WNKs) and two homologous Ste20-related kinases, SPAK and OSR1. Gain-of-function mutations within the WNK-SPAK/OSR1-NKCC2/NCC pathway lead to renal salt retention and hypertension, whereas loss-of-function mutations have been associated with salt-losing tubulopathies such as Bartter or Gitelman syndromes. A Bartter-like syndrome has been also described in patients carrying gain-of-function mutations in the CaSR gene. Recent work suggested that CaSR signals via the WNK-SPAK/OSR1 cascade to modulate salt reabsorption along the distal nephron. The review presented here summarizes the latest progress in understanding of functional interactions between CaSR and WNKs and their potential impact on the renal salt handling and blood pressure.
Highlights
Calcium homeostasis is critical to the intact cardiac rhythm and neuronal functions
The purpose of this review work is to summarize the available information on the role of calcium-sensing receptor (CaSR) and Ca2+ -signaling in the with-no-lysine [K] kinases (WNKs)-dependent regulation of distal salt reabsorption
Rat kidney sections for and a magnified insert; macula densa cells are flanked by lines, concomitant luminal Na+ -Cl− cotransporter (NCC) presence; the thick ascending limb (TAL)/distal convoluted tubule (DCT) transition is labeled by dashed line. (B)
Summary
Calcium homeostasis is critical to the intact cardiac rhythm and neuronal functions. Serum calcium levels are maintained within a narrow range of 2.2–2.6 mmol/L by orchestrated functions of many organs. The two transporters belong to the family of electroneutral cation-coupled chloride cotransporters and share the posttranslational regulation by phosphorylation or dephosphorylation of conserved N-terminal threonine or serine residues (for review [33]) Their activating phosphorylation is provided by a kinase cascade comprising chloride-sensitive with-no-lysine [K] kinases (WNK) and two downstream kinases with high degree of homology, the Ste20/SPS1-related proline-alanine-rich kinase (SPAK) and the oxidative stress responsive kinase 1 (OSR1) [33]. Systemic shifts of extracellular calcium [Ca2+ ] levels may affect [Ca2+ ]i in cells of the distal nephron via CaSR activity, modulating the renal salt handling In this context, early epidemiologic studies demonstrated increased incidence of hypertension in individuals with restricted dietary calcium intake (for review, [42]). The purpose of this review work is to summarize the available information on the role of CaSR and Ca2+ -signaling in the WNK-dependent regulation of distal salt reabsorption
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