Physiology and pathophysiology of the calcium-sensing receptor in the kidney

Abstract

The extracellular calcium-sensing receptor (CaSR) plays a major role in the maintenance of a physiological serum ionized calcium (Ca2+) concentration by regulating the circulating levels of parathyroid hormone. It was molecularly identified in 1993 by Brown et al. in the laboratory of Dr. Steven Hebert with an expression cloning strategy. Subsequent studies have demonstrated that the CaSR is highly expressed in the kidney, where it is capable of integrating signals deriving from the tubular fluid and/or the interstitial plasma. Additional studies elucidating inherited and acquired mutations in the CaSR gene, the existence of activating and inactivating autoantibodies, and genetic polymorphisms of the CaSR have greatly enhanced our understanding of the role of the CaSR in mineral ion metabolism. Allosteric modulators of the CaSR are the first drugs in their class to become available for clinical use and have been shown to treat successfully hyperparathyroidism secondary to advanced renal failure. In addition, preclinical and clinical studies suggest the possibility of using such compounds in various forms of hypercalcemic hyperparathyroidism, such as primary and lithium-induced hyperparathyroidism and that occurring after renal transplantation. This review addresses the role of the CaSR in kidney physiology and pathophysiology as well as current and in-the-pipeline treatments utilizing CaSR-based therapeutics.

Fig. 1.

Intrarenal localization and roles of the calcium-sensing receptor (CaSR). Cellular polarity of the CaSR is apical [in the proximal tubule and outer/inner medullary collecting duct (OMCD/IMCD)] and basolateral [in the thick ascending limb (TAL) and, occasionally, in the cortical collecting duct (CCD)]. Species differences exist in the distal convoluted tubule (DCT)/connecting segment (CNT), where receptor expression can be detected apically and/or basolaterally/intracellularly. PCT/PST, proximal convoluted/straight tubule; tDL/tAL, thin discending/ascending limb; MTAL/CTAL, medullary/cortical thick ascending limb; JGA: juxtaglomerular apparatus; TRPV5, transient receptor potential vanilloid 5; PMCA, plasma membrane Ca²⁺-ATPase; VitD, vitamin D; VDR, vitamin D receptor; NKCC2, Na⁺-K⁺-2Cl⁻ cotransporter 2; ROMK, renal outer medullary potassium K⁺ channel; PTH, parathyroid hormone; AQP2, aquaporin 2.