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Role of the Calcium-Sensing Receptor in Reducing the Risk for Calcium Stones

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Role of the Calcium-Sensing Receptor in Reducing the Risk for Calcium Stones CJASN ePress. Published on July 22, 2011 as doi: 10.2215/CJN.00480111 Role of the Calcium-Sensing Receptor in Reducing the Risk for Calcium Stones Kirsten Y. Renkema,*† Rene´J. M. Bindels,* and Joost G. J. Hoenderop* Summary -The tight control of blood Ca2؉ levels within a narrow range is essential for the performance of vital physio logic functions. Muscle contraction, neuronal excitation, and intracellular signaling processes acquisitively * 2؉ 2؉ Department of require Ca . It is the concerted action of intestine, bone, and kidney that controls the Ca balance through Physiology, Nijmegen 2؉ the regulation of intestinal absorption, bone (de)mineralization, and renal excretion of Ca , respectively. Centre for Molecular Along the nephron, fine-tuning of blood Ca2؉ levels takes place by Ca2؉ reabsorption. The calciotropic hor- Life Sciences, Radboud mones regulate Ca2؉ transport processes, leading to whole-body Ca2؉ homeostasis and, importantly, preserv- University Nijmegen ,2؉ 2؉ Medical Centre ing a constant Ca concentration in the blood. Defects in renal Ca handling can lead to hypercalciuria, Nijmegen, The consecutive kidney stone formation, and obstructive nephropathy. Here we give an overview of the key play- Netherlands; ؉ ers involved in normal Ca2 management and describe the in-depth investigations on a renal hypercalciuric †Department of Medical model of disease, the Trpv5 knockout mouse, which naturally displays molecular adaptations that prevent Genetics, University ,Ca2؉ precipitation in the kidney. Medical Center Utrecht Utrecht, The Clin J Am Soc Nephrol 6: 2076–2082, 2011. doi: 10.2215/CJN.00480111 Netherlands Correspondence: Prof. Introduction transport is taking place in the TALH as well is still Dr. J. G. J. Hoenderop, ϩ Maintenance of a normal calcium (Ca2 ) balance is questionable and needs further investigation. A three- Department of Physiology (286), accomplished by the concerted action of the intestine, step process, similar to the duodenal route, mediates Radboud University ϩ ϩ kidney, and bone. Disturbances in the Ca2 balance active Ca2 reabsorption in the DCT and CNT, in- Nijmegen Medical ϩ can result in symptoms including kidney stones, os- volving cell entry via the epithelial Ca2 channel Centre (RUNMC), P.O. ϩ teoporosis, and rickets. Ca2 is absorbed from the diet TRPV5, cytosolic transport via calbindin-D , and Box 9101, 6500 HB 28K Nijmegen, The in multiple segments of the small intestine (1). In the extrusion into the peritubular capillaries by the Netherlands. Phone: 2ϩ ϩ 2ϩ jejunum and ileum, passive absorption of Ca takes Na -Ca -exchanger (NCX1) and PMCA1B (1). 0031 24 36 13426; ϩ place in a paracellular manner along with sodium and TRPV5- and TRPV6-mediated active entry of Ca2 Fax: 0031 24 36 ϩ water uptake. Besides that, active Ca2 absorption is from the lumen into the cytosol of intestinal and 16413; E-mail: J.Hoenderop@fysiol. hormonally regulated and mainly occurs in the duo- renal epithelial cells, respectively, is tightly con- ϩ umcn.nl denum. The transcellular Ca2 uptake process in- trolled by a complex network of interacting pro- volves luminal entry into the cell through the epi- teins and calciotropics hormones, representing the ϩ ϩ thelial Ca2 channel, transient receptor potential rate-limiting step in transcellular Ca2 (re)absorp- ϩ ϩ vanilloid member 6 (TRPV6) (2). Ca2 is subse- tion and, thereby, fine-tuning overall body Ca2 ϩ quently bound by Ca2 binding proteins (calbin- balance. din-D9K) and shuttled to the basolateral side of the cell. The transcellular route is fulfilled by active Classic Calciotropic Hormones in Control ϩ ϩ Ca2 extrusion to the blood via the plasma mem- Ca2 homeostasis is preserved by the classically ϩ brane Ca2 -ATPase (PMCA1B). In the circulation, recognized calciotropic hormones vitamin D 2ϩ 45% of Ca is present as the free ionized form, while (1,25(OH)2D3), parathyroid hormone (PTH), and cal- 45% is bound to proteins. The remaining 10% forms citonin (4). Central to this process is the G-protein ϩ complexes with anions, including citrate, sulfate, and coupled Ca2 -sensing receptor (CaSR) in the parathy- ϩ phosphate. The majority of Ca2 is stored in the skel- roid glands that detects changes in blood ionized ϩ eton. Taking a closer look at the kidney, it is appreci- Ca2 levels (5). In response to an alteration in the ϩ ϩ ated that blood Ca2 is filtered at the glomerulus and blood Ca2 levels, the CaSR modulates PTH release thereby enters the lumen of the renal tubule. Along into the circulation. Specifically, the activation of the ϩ ϩ the course of the nephron passive, paracellular Ca2 CaSR by increased circulating Ca2 levels suppresses reabsorption occurs in the proximal tubule (PT) and PTH release and stimulates the secretion of calcitonin the thick ascending limb of Henle (TALH) (1). A small from the thyroid gland. Calcitonin reduces osteoclast- ϩ (10 to 15%), highly regulated quantity of Ca2 is mediated bone resorption and thereby promotes a ϩ reabsorbed in the distal convoluted tubule (DCT) and decrease in blood Ca2 levels (6). Gain-of-function the connecting tubule (CNT) in an active transcellular mutations in the CASR gene lower blood PTH levels, ϩ ϩ transport process (3). Whether transcellular Ca2 hampering Ca2 (re)absorption and thereby evoking 2076 Copyright © 2011 by the American Society of Nephrology www.cjasn.org Vol 6 August, 2011 Clin J Am Soc Nephrol 6: 2076–2082, August, 2011 CaSR and renal calcium stones, Renkema, Bindels, and Hoenderop 2077 ϩ hypocalcemia in humans (7). A hypocalcemic state does exerts an effect on renal Ca2 handling via TRPV5 upregu- not activate the CaSR, leading to PTH secretion. PTH stim- lation at the transcriptional level in rats, independent of 2ϩ 2ϩ ulates active Ca reabsorption, thereby enabling Ca 1,25(OH)2D3 (17). Furthermore, estrogen deficiency is ϩ ϩ retention in the body. Furthermore, PTH enhances Ca2 known to result in a negative Ca2 balance and bone loss mobilization from bone and the conversion of inact- in postmenopausal women (18). These results partly ex- ϩ ive vitamin D to its biologically active form— plain gender differences in renal Ca2 handling (19). The 1,25(OH)2D3—by the renal cytochrome P450 enzyme tissue kallikrein (TK) hormone is secreted into the pro- ␣ ␣ 25-hydroxyvitamin D3-1 -hydroxylase (1 -OHase) in urine by renal tubular epithelial cells. The TK knockout ϩ the kidney. Previous studies demonstrated that mouse demonstrates renal Ca2 wasting (20). In 2006, 1,25(OH)2D3 facilitates vitamin D receptor (VDR)– Gkika et al. described the mechanism through which TK ϩ mediated gene transcription that evokes transcription of stimulates TRPV5-mediated active Ca2 reabsorption. TK ϩ ϩ Ca2 transporter encoding genes in Ca2 transporting activates the bradykinin receptor, thereby stimulating the cells, established by the interaction of the 1,25(OH)2D3- phospholipase C/1,2-diacylglycerol/protein kinase C VDR complex with vitamin D responsive elements (PLC/DAG/PKC) pathway (21). As a result, TRPV5 chan- (VDREs) in the promoter regions of target genes (8). Mul- nels show an increased expression on the plasma mem- ϩ tiple intestinal and renal Ca2 transporter encoding genes brane, probably due to an inhibition of TRPV5 endocytosis. 2ϩ were shown to contain VDREs, indicating 1,25(OH)2D3 as Hence, TK regulates the Ca balance in a positive direc- ϩ ϩ an important stimulator of Ca2 (re)absorption (9). As a tion and thus preserves Ca2 in the body. The antiaging consequence, a lack of 1,25(OH)2D3 could cause distur- hormone Klotho is a transmembrane protein with an ex- ϩ bances in the Ca2 balance. For example, bone diseases like tracellular domain that is secreted into blood, urine, and osteoporosis, osteomalacia, and rickets occur as a conse- cerebrospinal fluid. Chang et al. demonstrated a stimula- ϩ quence of vitamin D deficiency, occurring during malnu- tory effect of Klotho on TRPV5-mediated active Ca2 ϩ trition, aging, and menopause. Humans with a defect in transport (22). Klotho was shown to alter the Ca2 perme- VDR function show bone abnormalities known as vitamin ability of the renal luminal membrane by the removal of D–dependent rickets type II (10). In the past, genetically alpha2,6-linked sialic acids (23). Thereby, Klotho can reg- modified mouse models were generated in which the ulate the cell surface retention of functional TRPV5, sub- 2ϩ 1,25(OH)2D3 endocrine system was inactivated. Two re- stantiating the important role of Klotho in Ca homeosta- search groups independently created the 1␣-OHase knock- sis. Moreover, the phenotypic characterization of the Klotho out mouse (11,12). Phenotypic analysis showed that these knockout mouse revealed hypercalciuria, hypervitamino- mice were unable to generate 1,25(OH)2D3, leading to se- sis D, infertility, short life span, and bone aberrations vere hypocalcemia, secondary hyperparathyroidism, de- clearly overlapping with symptoms presented by Trpv5 ϩ creased bone mineral density, rickets, and growth retarda- knockout mice (24). Although large variations in Ca2 ϩ ϩ tion. Intestinal and renal Ca2 transporters were intake produce only small alterations in blood Ca2 levels, downregulated, whereas repletion with 1,25(OH)2D3 led to due to the tight control by the above-mentioned key play- ϩ ϩ the restoration of renal and intestinal Ca2 transporter ers, previous investigations demonstrated that high Ca2 ϩ ϩ expression levels and normalization of blood Ca2 levels intake is an important regulator of renal Ca2 transport (13). These experiments confirmed the essential role of protein expression as well, specifically in a 1,25(OH)2D3- 2ϩ Ca transport proteins in 1,25(OH)2D3-mediated active deficient state, thereby contributing to the maintenance of ϩ ϩ Ca2 (re)absorption. Similarly, VDR knockout mice dis- a normal body Ca2 balance (13). played hypocalcemia, bone degradation, increased blood PTH levels, and hypervitaminosis D, due to a lack of VDR-mediated gene transcription (14).
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