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

Through regulation of excretion, the kidney shares responsibility for the metabolic balance of calcium (Ca(2+)) with several other tissues including the GI tract and bone. The balances of Ca(2+) and phosphate (PO4), magnesium (Mg(2+)), 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 Ca(2+) metabolism (Familial Hypocalciuric Hypercalcemia, FHH, and Autosomal Dominant Hypocalcemia, ADH) made it clear that extracellular Ca(2+) (Ca(2+)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 Ca(2+) on the kidney (wasting of Na(+), K(+), Cl(-), Ca(2+), Mg(2+) 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 Ca(2+) 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 Ca(2+) in the circulation and urine in a manner that assures a narrow range of Ca(2+)o in the blood and avoids excessively high concentrations of Ca(2+) in the urine.