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Control of renal calcium, phosphate, Electrolyte, and water excretion by the calcium-sensing receptor

https://doi.org/10.1016/j.beem.2013.04.009Get rights and content

Through regulation of excretion, the kidney shares responsibility for the metabolic balance of calcium (Ca2+) with several other tissues including the GI tract and bone. The balances of Ca2+ and phosphate (PO4), magnesium (Mg2+), sodium (Na+), potassium (K+), chloride (Cl), and water (H2O) are linked via regulatory systems with overlapping effects and are also controlled by systems specific to each of them. Cloning of the calcium-sensing receptor (CaSR) along with the recognition that mutations in the CaSR gene are responsible for two familial syndromes characterized by abnormalities in the regulation of PTH secretion and Ca2+ metabolism (Familial Hypocalciuric Hypercalcemia, FHH, and Autosomal Dominant Hypocalcemia, ADH) made it clear that extracellular Ca2+ (Ca2+o) participates in its own regulation via a specific, receptor-mediated mechanism. Demonstration that the CaSR is expressed in the kidney as well as the parathyroid glands combined with more complete characterizations of FHH and ADH established that the effects of elevated Ca2+ on the kidney (wasting of Na+, K+, Cl, Ca2+, Mg2+ and H2O) are attributable to activation of the CaSR. The advent of positive and negative allosteric modulators of the CaSR along with mouse models with global or tissue-selective deletion of the CaSR in the kidney have allowed a better understanding of the functions of the CaSR in various nephron segments. The biology of the CaSR is more complicated than originally thought and difficult to define precisely owing to the limitations of reagents such as anti-CaSR antibodies and the difficulties inherent in separating direct effects of Ca2+ on the kidney mediated by the CaSR from associated CaSR-induced changes in PTH. Nevertheless, renal CaSRs have nephron-specific effects that contribute to regulating Ca2+ in the circulation and urine in a manner that assures a narrow range of Ca2+o in the blood and avoids excessively high concentrations of Ca2+ in the urine.

Introduction

The calcium-sensing receptor (CaSR), a G protein-coupled receptor, is best known and understood for its control of PTH synthesis and secretion in response to changes in Ca2+o, but it also has prominent, tubule-specific effects in the kidney (Fig. 1).1, 2 CaSR activation in the kidney results in a marked diuresis of water, Ca2+ and salts that can reach the point of volume depletion and hypotension. These effects are in contrast to those of other G protein-coupled receptors along the nephron (e.g., AT1, V1, eicosanoid receptors) that also act via Gαi and Gαq but either have a minimal effect on volume or cause volume retention. Some of the effects of the CaSR in the kidney appear to affect Ca2+ and PO4 metabolism by antagonizing the effects of PTH on tubular transport of these ions, but the major renal effects of the CaSR are through direct effects on the renal tubular transport of Ca2+, Mg2+, Na+, K+, Cl, H+, and H2O. Activation of the CaSR (hypercalcemia or mutations) reduces distal nephron reabsorption of Na+, K+, Cl, and H2O. The expression of the CaSR along the nephron, in the gills of fish, and in the GI tract of aquatic animals that regulate body solute content indicates that it may have a physiologic role in the control of NaCl transport in addition to regulating Ca2+ and Mg2+ transport.3, 4 In land mammals, increased salt and water excretion may be tied to hypercalcemia and resultant increases in Ca2+ excretion in order to prevent the occurrence of high concentrations of Ca2+ in the urine with the accompanying risk of precipitation, nephrocalcinosis, and stone formation.

Section snippets

Human studies

The role of the CaSR in human physiology has been demonstrated in studies of loss- and gain-of-function CaSR mutations, and in studies employing agents that increase or inhibit CaSR activity.

Physiological and pharmacological regulators of CaSR activity

Divalent cations activate the CaSR in the low millimolar range i.e., at physiologically relevant concentrations.23 The CaSR may, in fact, respond to the sum of polycations in its local environment rather than extracellular Ca2+ concentration alone.23

The CaSR can signal in a paracrine manner, possibly similar to that of purinergic receptors.24 Intracellular Ca2+ rises and then falls following receptor-mediated activation of many cell-signaling systems. The fall occurs in part because Ca2+ is

Expression pattern of the CaSR along the nephron and segment-specific transport functions

A significant limitation in studies of CaSR function in the kidney has arisen from the difficulty of clearly defining the patterns of CaSR expression along the nephron. Although all studies agree that the CaSR is expressed along the basolateral membrane of the thick ascending limb of Henle, a key site of regulated calcium reabsorption (Fig. 1),28, *29, *30, 31, 32, 33 different groups have reached different conclusions regarding the nature and level of CaSR expression in other sites despite the

Conclusion

The kidney is an essential component of the system that regulates body Ca2+ metabolism, and it does so by controlling urinary Ca2+ excretion. The clinical importance of the CaSR in the kidney relates to its responsibility not only for regulating whole body Ca2+ balance, but also for maintaining the solubility of Ca2+ in the urine and reducing the risk of nephrolithiasis. Hypercalciuria is the most common finding in patients with nephrolithiasis. Hypercalciuria may originate from increases in

Acknowledgements

This work was supported by a grant from the National Institutes of Health (DK-59985) to R.T. Miller, a VA Merit Review to R. T. Miller, the U. T. Southwestern O’Brien Center for Kidney Disease, and the Charles and Jane Pak Center of Mineral Metabolism and Clinical Research.

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