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• W2114781384 abstract "Ca2+ homeostasis is an important factor, which is underlined by the numerous clinical symptoms that involve Ca2+ deficiencies. The overall Ca2+ balance is maintained by the concerted action of Ca2+ absorption in the intestine, reabsorption in the kidney, and exchange from bone, which are all under the control of the calciotropic hormones that are released upon a demand for Ca2+. In the kidney, these calciotropic hormones affect active Ca2+ reabsorption, which consists of TRPV5 as the apical entry gate for Ca2+ influx, calbindin-D28K as an intracellular ferry for Ca2+ and, NCX1 and PMCA1b for extrusion of Ca2+ across the basolateral membrane. This review highlights the action of hormones on renal Ca2+ handling and focuses on the coordinated control of the renal Ca2+ transport proteins. Parathyroid hormone stimulates renal Ca2+ handling by regulating active Ca2+ reabsorption on both the genomic and non-genomic level. Estrogens harbor calciotropic hormone characteristics positively regulating the expression of TRPV5, independently of vitamin D. Besides having a strong regulatory effect on the expression of the intestinal Ca2+ transport proteins, vitamin D contributes to the overall Ca2+ balance by enhancing the expression of the Ca2+ transport machinery in the kidney. Dietary Ca2+ is involved in regulating its own handling by controlling the expression of the renal Ca2+ transport proteins. Thus, the magnitude of Ca2+ entry via TRPV5 controls the expression of the other Ca2+ transport proteins underlining the gatekeeper function of this Ca2+ channel in the renal Ca2+ handling. Ca2+ homeostasis is an important factor, which is underlined by the numerous clinical symptoms that involve Ca2+ deficiencies. The overall Ca2+ balance is maintained by the concerted action of Ca2+ absorption in the intestine, reabsorption in the kidney, and exchange from bone, which are all under the control of the calciotropic hormones that are released upon a demand for Ca2+. In the kidney, these calciotropic hormones affect active Ca2+ reabsorption, which consists of TRPV5 as the apical entry gate for Ca2+ influx, calbindin-D28K as an intracellular ferry for Ca2+ and, NCX1 and PMCA1b for extrusion of Ca2+ across the basolateral membrane. This review highlights the action of hormones on renal Ca2+ handling and focuses on the coordinated control of the renal Ca2+ transport proteins. Parathyroid hormone stimulates renal Ca2+ handling by regulating active Ca2+ reabsorption on both the genomic and non-genomic level. Estrogens harbor calciotropic hormone characteristics positively regulating the expression of TRPV5, independently of vitamin D. Besides having a strong regulatory effect on the expression of the intestinal Ca2+ transport proteins, vitamin D contributes to the overall Ca2+ balance by enhancing the expression of the Ca2+ transport machinery in the kidney. Dietary Ca2+ is involved in regulating its own handling by controlling the expression of the renal Ca2+ transport proteins. Thus, the magnitude of Ca2+ entry via TRPV5 controls the expression of the other Ca2+ transport proteins underlining the gatekeeper function of this Ca2+ channel in the renal Ca2+ handling. Ion homeostasis in our body is tightly regulated and disturbances in its balance may lead to pathogenesis. The kidney plays a vital role in this process by balancing the dietary intake with the reabsorption from the pro-urine. One of these ions is Ca2+ that plays a key role in many physiological processes like hormone secretion, muscle contraction, bone formation, nerve conduction, exocytosis, and (in)activation of enzymes. The body, therefore, carefully regulates the plasma concentration of Ca2+ within a narrow range by the concerted action of intestinal Ca2+ absorption, exchange of Ca2+ from bone and renal Ca2+ reabsorption. An intrinsic physiological mechanism is sensing the Ca2+ demand by a specialized Ca2+-sensing receptor that activates a cascade of pathways, eventually leading to the synthesis and release of calciotropic hormones, including 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), parathyroid hormone (PTH) and calcitonin. These hormones act in a paracrine fashion, efficiently regulating the above-described Ca2+ transport processes. In the kidney, Ca2+ can re-enter the blood by paracellular (passive) as well as transcellular (active) Ca2+ reabsorption and the latter is the main target for the calciotropic hormones. Active Ca2+ reabsorption comprises a sequence of processes restricted to the distal convoluted tubule (DCT) and the connecting tubule (CNT). At the cellular level, Ca2+ enters the renal epithelial cell via the highly Ca2+-selective channel TRPV5 because of a steep inward electrochemical gradient across the apical membrane. In the cell, Ca2+ is bound to calbindin-D28K that ferries Ca2+ from the apical side to the basolateral side where the Na+/Ca2+-exchanger (NCX1) and the plasma membrane ATPase (PMCA1b) extrude Ca2+ into the blood compartment (Figure 1). In the intestine, a similar mechanism for transcellular Ca2+ absorption occurs with TRPV6 as the gatekeeper, calbindin-D9K as intracellular ferry of Ca2+ and PMCA1b as the extrusion mechanism. This review highlights the hormonal regulation of Ca2+ reabsorption in the kidney and focuses on the coordinated expression of the Ca2+ transport proteins TRPV5, calbindin-D28K, NCX1, and PMCA1b as the underlying mechanism contributing to the Ca2+ balance. Primary hyperparathyroidism is characterized by PTH levels that are inappropriate to the level of plasma Ca2+ and is one of the endocrine disorders that underline the importance of PTH in maintaining the Ca2+ balance. In addition, mutations in the Ca2+-sensing receptor, which couples the plasma Ca2+ levels to the production and secretion of PTH from the thyroid glands, were identified in patients with familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism (inactivating mutations),1.Pollak M.R. Brown E.M. Chou Y.H. et al.Mutations in the human Ca2+-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.Cell. 1993; 75: 1297-1303Abstract Full Text PDF PubMed Scopus (858) Google Scholar and autosomal-dominant hypocalcemia (activating mutations).2.Pollak M.R. Brown E.M. Estep H.L. et al.Autosomal dominant hypocalcemia caused by a Ca2+-sensing receptor gene mutation.Nat Genet. 1994; 8: 303-307Crossref PubMed Scopus (499) Google Scholar From the clinical symptoms of these PTH-related disorders, including hypo- or hypercalciuria and renal stone formation, it is evident that renal Ca2+ handling is also affected. PTH receptors have been detected throughout the nephron including DCT and CNT, thus enabling the body to directly control active Ca2+ reabsorption in the kidney via PTH.3.Hoenderop J.G. Nilius B. Bindels R.J. Calcium absorption across epithelia.Physiol Rev. 2005; 85: 373-422Crossref PubMed Scopus (610) Google Scholar In addition, genetic ablation of Ca2+-sensing receptor resulted in hyperparathyroidism and hypercalcemia, accompanied by an upregulation of TRPV5 and TRPV6 in the kidney and intestine, respectively (Table 1).4.Kos C.H. Karaplis A.C. Peng J.B. et al.The calcium-sensing receptor is required for normal calcium homeostasis independent of parathyroid hormone.J Clin Invest. 2003; 111: 1021-1028Crossref PubMed Scopus (168) Google Scholar To understand the molecular regulation of the Ca2+ transport proteins by PTH, parathyroidectomy was performed in rats.5.van Abel M. Hoenderop J.G. van der Kemp A.W. et al.Coordinated control of renal Ca2+ transport proteins by parathyroid hormone.Kidney Int. 2005; 68: 1708-1721Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar The effectiveness of this treatment was evident from the marked reduction of PTH levels and hyperphosphatemia, a well-known symptom in hypoparathyroidism. Moreover, parathyroidectomy reduced the expression of TRPV5, calbindin-D28K, and NCX1. This decline in expression of the renal Ca2+ transport proteins resulted in decreased active Ca2+ reabsorption and the development of hypocalcemia. PTH supplementation in these parathyroidectomized rats resulted in normalization of the renal Ca2+ transport protein expression levels and increased the plasma Ca2+ concentration.5.van Abel M. Hoenderop J.G. van der Kemp A.W. et al.Coordinated control of renal Ca2+ transport proteins by parathyroid hormone.Kidney Int. 2005; 68: 1708-1721Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar In addition, the regulation by PTH was investigated in primary cultures of rabbit CNT and cortical collecting duct (CCD) cells.5.van Abel M. Hoenderop J.G. van der Kemp A.W. et al.Coordinated control of renal Ca2+ transport proteins by parathyroid hormone.Kidney Int. 2005; 68: 1708-1721Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar PTH resulted in an elevated expression of the Ca2+ transport proteins TRPV5, calbindin-D28K, NCX1, and PMCA1b in these renal cultures. Taken together, these results indicate that PTH stimulates renal Ca2+ handling by co-regulating the expression of the Ca2+ transport proteins.Table 1Coordinated regulation of the Ca2+ transport proteinsKidneyIntestineTRPV5Calbindin-D28KNCX1PMCA1bTRPV6Calbindin-D9KPMCA1bReferencePTH CaSRaGenetic ablation of the CaSR resulted in a severe hyperparathyroidism. See text for details.↑NMNMNM↑NMNM4 Parathyroidectomy↓↓↓=NMNMNM5 Parathyroidectomy+PTH replacement therapy↑↑↑=NMNMNM5 PTH supplementation↑↑↑↑NMNMNM5Estrogens Estrogen receptor-α−/−↓↓↓↓↓==3 Ovariectomy====NMNMNM3 Ovariectomy+replacement therapy↑↑/=↑/=↑/=↑↑/ =↑/=3 Estrogen supplementation in 1α-OHase−/−↑===↑NMNM3 Estrogen supplementation in ovariectomized VDR−/−↑===↑==3Vitamin D Vitamin D deficiency↓NMNMNMNMNMNM3 1α-OHase−/−↓↓↓=NMNMNM14/3 VDR−/−↓===↓↓=15 1,25(OH)2D3 supplementation in vitamin D deficiency↑↑NMNMNMNMNM3Ca2+ Ca2+ supplementation in 1α-OHase−/−↑↑↑↑NMNMNM3Miscellaneous TRPV5−/−ND↓↓=↑↑↑16Overview of the different studies investigating the expression of the Ca2+ transport proteins in the kidney and intestine. Genetic ablation, dietary, and hormonal Ca2+ alterations demonstrated a concomitant regulation in expression of the renal and intestinal Ca2+ transport proteins.↑, upregulation; ↓, downregulation; =, no change in expression; NM, not measured; ND not detectable; PTH, parathyroid hormone; CaSR, Ca2+-sensing receptor; 1α-OHase, 25-hydroxyvitamin D3-1α-hydroxylase.a Genetic ablation of the CaSR resulted in a severe hyperparathyroidism. See text for details. Open table in a new tab Overview of the different studies investigating the expression of the Ca2+ transport proteins in the kidney and intestine. Genetic ablation, dietary, and hormonal Ca2+ alterations demonstrated a concomitant regulation in expression of the renal and intestinal Ca2+ transport proteins. ↑, upregulation; ↓, downregulation; =, no change in expression; NM, not measured; ND not detectable; PTH, parathyroid hormone; CaSR, Ca2+-sensing receptor; 1α-OHase, 25-hydroxyvitamin D3-1α-hydroxylase. Regulation of expression of the Ca2+ transport proteins, however, is a relatively slow process whereas a fast non-genomic response operates on a time scale that is sufficient for an immediate increase of Ca2+ reabsorption. An established pathway for short-term PTH-stimulated active Ca2+ reabsorption in the kidney is activation of adenylyl cyclase, accumulation of cyclic adenosine 3′,5′ monophosphate and subsequent stimulation of protein kinase A. PTH addition to perfused rabbit CNT and primary cultures of rabbit CNT and CCD resulted in a rise of cytosolic cyclic adenosine 3′,5′ monophosphate levels accompanied by an increase in the cytosolic Ca2+ concentration and transcellular Ca2+ transport.6.Bindels R.J. Hartog A. Timmermans J. et al.Active Ca2+ transport in primary cultures of rabbit kidney CCD: stimulation by 1,25-dihydroxyvitamin D3 and PTH.Am J Physiol. 1991; 261: F799-F807PubMed Google Scholar, 7.Lau K. Bourdeau J.E. Evidence for cAMP-dependent protein kinase in mediating the parathyroid hormone-stimulated rise in cytosolic free calcium in rabbit connecting tubules.J Biol Chem. 1989; 264: 4028-4032PubMed Google Scholar Moreover, protein kinase A inhibitors reduced the PTH-mediated rise of cytosolic Ca2+, which suggests that cyclic adenosine 3′,5′ monophosphate-dependent phosphorylation is an essential step in short-term PTH stimulation. In addition to cyclic adenosine 3′,5′ monophosphate, a prominent role for protein kinase C was demonstrated in the short-term PTH response.8.Hoenderop J.G. De Pont J.J. Bindels R.J. et al.Hormone-stimulated Ca2+ reabsorption in rabbit kidney cortical collecting system is cAMP-independent and involves a phorbol ester-insensitive PKC isotype.Kidney Int. 1999; 55: 225-233Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar Thus, besides a genomic effect, PTH can stimulate Ca2+ reabsorption directly via a short-term mechanism involving protein kinase A and protein kinase C. Taken together, these studies reveal that PTH-dependent stimulation of transcellular Ca2+ reabsorption in the kidney occurs via both genomic and non-genomic pathways. An increased risk for osteoporosis in postmenopausal women is associated with estrogen deficiency. Furthermore, estrogen deficiency is associated with renal Ca2+ wasting and intestinal Ca2+ malabsorption that can be restored by estrogen replacement therapy.9.Prince R.L. Smith M. Dick I.M. et al.Prevention of postmenopausal osteoporosis. A comparative study of exercise, calcium supplementation, and hormone-replacement therapy.N Engl J Med. 1991; 325: 1189-1195Crossref PubMed Scopus (477) Google Scholar From these findings, the physiological relevance of estrogens in maintaining the Ca2+ balance is feasible. In addition, this suggests that estrogens can comply with the action of the calciotropic hormones, regulating the expression of the renal Ca2+ transport proteins. Estrogen receptors have been detected in DCT and CNT, thus enabling the body to directly regulate active Ca2+ reabsorption in the kidney by estrogen.3.Hoenderop J.G. Nilius B. Bindels R.J. Calcium absorption across epithelia.Physiol Rev. 2005; 85: 373-422Crossref PubMed Scopus (610) Google Scholar Estrogen replacement therapy in ovariectomized rats revealed an increase in the expression of TRPV5, calbindin-D28K, NCX1, and PMCA1b in the kidney suggesting an important role for this hormone in regulating Ca2+ reabsorption.3.Hoenderop J.G. Nilius B. Bindels R.J. Calcium absorption across epithelia.Physiol Rev. 2005; 85: 373-422Crossref PubMed Scopus (610) Google Scholar In addition, genetic ablation of the estrogen receptor-α in mice decreased the expression of the aforementioned renal Ca2+ transport proteins. In principle, these effects could be explained by estrogen-dependent vitamin D activation. This possibility was investigated in vitamin D-deficient animal models. Estrogen supplementation in 25-hydroxyvitamin D3-1α-hydroxylase (1α-OHase) knockout mice increased the expression of TRPV5 in the kidney, whereas the expression of the other Ca2+ transport proteins remained unaltered.3.Hoenderop J.G. Nilius B. Bindels R.J. Calcium absorption across epithelia.Physiol Rev. 2005; 85: 373-422Crossref PubMed Scopus (610) Google Scholar In the intestine, estrogens regulate the expression of TRPV6 in a vitamin D-independent manner, which became clear from estrogen supplementation in vitamin D receptor and 1α-OHase knockout mice. This resulted in an upregulation of duodenal TRPV6, whereas the expression of calbindin-D9K and PMCA1b was not altered.3.Hoenderop J.G. Nilius B. Bindels R.J. Calcium absorption across epithelia.Physiol Rev. 2005; 85: 373-422Crossref PubMed Scopus (610) Google Scholar Thus, estrogens harbor calciotropic hormone characteristics regulating the expression of TRPV5 and TRPV6 in the kidney and intestine, respectively. The active form of vitamin D, 1,25(OH)2D3, is an important hormone in the body Ca2+ homeostasis. This is reflected by several vitamin D-related disorders with symptoms like rickets and hypercalciuria. Inactivating mutations in 1α-OHase are associated with vitamin D-deficiency rickets type 110.Kitanaka S. Takeyama K. Murayama A. et al.Inactivating mutations in the 25-hydroxyvitamin D3 1alpha-hydroxylase gene in patients with pseudovitamin D-deficiency rickets.N Engl J Med. 1998; 338: 653-661Crossref PubMed Scopus (275) Google Scholar and mutations in the vitamin D receptor are associated with hypocalcemic rickets.11.Hughes M.R. Malloy P.J. Kieback D.G. et al.Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets.Science. 1988; 242: 1702-1705Crossref PubMed Scopus (397) Google Scholar Active Ca2+ reabsorption is a main target for 1,25(OH)2D3, as illustrated by 1,25(OH)2D3-stimulated Ca2+ transport in primary cultures of rabbit CNT and CCD cells and human intestinal Caco-2 cells.6.Bindels R.J. Hartog A. Timmermans J. et al.Active Ca2+ transport in primary cultures of rabbit kidney CCD: stimulation by 1,25-dihydroxyvitamin D3 and PTH.Am J Physiol. 1991; 261: F799-F807PubMed Google Scholar, 12.Fleet J.C. Eksir F. Hance K.W. et al.Vitamin D-inducible calcium transport and gene expression in three Caco-2 cell lines.Am J Physiol Gastrointest Liver Physiol. 2002; 283: G618-625Crossref PubMed Scopus (94) Google Scholar Strikingly, microarray analysis of 1,25(OH)2D3-stimulated carcinoma cells revealed TRPV6 as one of the most highly vitamin D-responsive genes.13.Wang T.T. Tavera-Mendoza L.E. Laperriere D. et al.Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes.Mol Endocrinol. 2005; 19: 2685-2695Crossref PubMed Scopus (443) Google Scholar Evidence for 1,25(OH)2D3-controlled expression of the renal Ca2+ transport proteins came from rats that were raised on a vitamin D-deficient diet. This diet decreased the renal expression of TRPV5, which was accompanied by a marked drop in plasma Ca2+ levels. In addition, genetic ablation of 1α-OHase in mice resulted in severe hypocalcemia, hyperparathyroidism, bone abnormalities, and retarded growth.14.Dardenne O. Prud'homme J. Arabian A. et al.Targeted inactivation of the 25-hydroxyvitamin D3-1(alpha)-hydroxylase gene (CYP27B1) creates an animal model of pseudovitamin D-deficiency rickets.Endocrinology. 2001; 142: 3135-3141Crossref PubMed Scopus (286) Google Scholar In line with the development of hypocalcemia is the diminished Ca2+ reabsorption in the kidney, presumably as a result of the downregulated expression of the Ca2+ transport proteins TRPV5, calbindin-D28K, and NCX1.3.Hoenderop J.G. Nilius B. Bindels R.J. Calcium absorption across epithelia.Physiol Rev. 2005; 85: 373-422Crossref PubMed Scopus (610) Google Scholar Supplementation of 1,25(OH)2D3 restored the expression of the renal Ca2+ transport proteins and normalized the hypocalcemia.3.Hoenderop J.G. Nilius B. Bindels R.J. Calcium absorption across epithelia.Physiol Rev. 2005; 85: 373-422Crossref PubMed Scopus (610) Google Scholar Thus, vitamin D is of fundamental importance for the regulation of renal Ca2+ transport proteins and the maintenance of a normal Ca2+ balance. Mice lacking TRPV5 display robust renal Ca2+ wasting because of impaired Ca2+ reabsorption in the DCT and CNT.15.Hoenderop J.G. van Leeuwen J.P. van der Eerden B. et al.Renal Ca2+ wasting, hyperabsorption and reduced bone thickness in mice lacking TRPV5.J Clin Invest. 2003; 112: 1906-1914Crossref PubMed Scopus (367) Google Scholar In addition, elevated 1,25(OH)2D3 plasma levels, intestinal Ca2+ hyperabsorption, and reduced bone thickness were demonstrated. Besides the decreased storage of Ca2+ in bone, compensatory hyperabsorption of Ca2+ in the intestine prevented hypocalcemia in these knockout mice. The underlying mechanism of this compensatory hyperabsorption is hypervitaminosis D, which increases the expression of the intestinal Ca2+ transport proteins TRPV6, calbindin-D9K, and PMCA1b.15.Hoenderop J.G. van Leeuwen J.P. van der Eerden B. et al.Renal Ca2+ wasting, hyperabsorption and reduced bone thickness in mice lacking TRPV5.J Clin Invest. 2003; 112: 1906-1914Crossref PubMed Scopus (367) Google Scholar This finding indicates that a renal Ca2+ leak because of the absence of TRPV5 triggers a rescue mechanism resulting in an increased production of vitamin D stimulating intestinal Ca2+ absorption. The absence of hypervitaminosis D in the recently developed 1α-OHase and TRPV5 double knockout (1α-OHase−/−/TRPV5−/−) mice, resulted in hypocalcemia and thus suggests that the elevated level of 1,25(OH)2D3 in the TRPV5−/− mice is responsible for the upregulation of intestinal Ca2+ transport proteins and the resulting Ca2+ hyperabsorption.16.Renkema K.Y. Nijenhuis T. van der Eerden B.C. et al.Hypervitaminosis D mediates compensatory Ca2+ hyperabsorption in TRPV5 knockout mice.J Am Soc Nephrol. 2005; 16: 3188-3195Crossref PubMed Scopus (68) Google Scholar The absence of hyperabsorption in 1α-OHase−/−/TRPV5−/− mice generated in a more aggravated phenotype compared to TRPV5 ablation. Thus, 1,25(OH)2D3 is crucial to compensate for the renal Ca2+ leak and to maintain normal plasma Ca2+ levels in TRPV5−/− mice. Importantly, PTH levels in these knockout models are comparable to wild-type littermates, indicating that the observed regulation is not because of altered PTH levels. Hereditary hypocalcemic vitamin D-resistant rickets, which are caused by a genetic defect in the VDR gene, are treated with a high dietary Ca2+ load.17.van Cromphaut S. Dewerchin M. Hoenderop J.G. et al.Active duodenal calcium absorption in vitamin D receptor-knock out mice: functional and molecular aspects.Proc Natl Acad Sci USA. 2001; 98: 13324-13329Crossref PubMed Scopus (441) Google Scholar This suggests that dietary Ca2+ can act as an additional regulatory mechanism of Ca2+ handling independent of vitamin D. From a molecular point of view, dietary Ca2+ affects the Ca2+ balance by regulating the expression of the renal and intestinal Ca2+ transport proteins. This is evident from high dietary Ca2+ supplementation in mice which, among others, resulted in a decreased TRPV5 and TRPV6 expression.3.Hoenderop J.G. Nilius B. Bindels R.J. Calcium absorption across epithelia.Physiol Rev. 2005; 85: 373-422Crossref PubMed Scopus (610) Google Scholar This decline in expression is likely mediated by the accompanied decrease in 1,25(OH)2D3 levels. However, in 1α-OHase knockout mice a high dietary Ca2+ load normalized the plasma Ca2+ concentration as well as the expression of TRPV5, calbindin-D28K, NCX1, and PMCA1b.3.Hoenderop J.G. Nilius B. Bindels R.J. Calcium absorption across epithelia.Physiol Rev. 2005; 85: 373-422Crossref PubMed Scopus (610) Google Scholar Likewise, in mice that lack vitamin D receptor an increased dietary Ca2+ intake upregulates the expression of TRPV5 in the kidney.17.van Cromphaut S. Dewerchin M. Hoenderop J.G. et al.Active duodenal calcium absorption in vitamin D receptor-knock out mice: functional and molecular aspects.Proc Natl Acad Sci USA. 2001; 98: 13324-13329Crossref PubMed Scopus (441) Google Scholar In addition, the expression of TRPV6 in the intestine was increased. Taken together, dietary Ca2+ regulates the expression of the Ca2+ transport proteins, independent of 1,25(OH)2D3. Various studies exploring the regulatory role of 1,25(OH)2D3, estrogens, PTH, and dietary Ca2+ revealed a concomitant regulation of the renal Ca2+ transport proteins. Additional evidence for 1,25(OH)2D3- and PTH-independent regulation of the Ca2+ balance was obtained from TRPV5 knockout mice. Downregulation of the vitamin D-dependent Ca2+ transport proteins calbindin-D28K and NCX1 in kidneys of these knockout mice despite elevated levels of 1,25(OH)2D3 suggests that TRPV5 is primarily involved in the regulation of the Ca2+ transport proteins expression in the kidney independent of 1,25(OH)2D3. An interesting question is how the expression of TRPV5 specifically coordinates the Ca2+ transport machinery. Because TRPV5 is the gatekeeper controlling the apical Ca2+ influx, it is feasible that the magnitude of Ca2+ influx through TRPV5 determines the expression of the Ca2+ transport proteins. This hypothesis was recently investigated using primary cultures of rabbit CNT and CCD.5.van Abel M. Hoenderop J.G. van der Kemp A.W. et al.Coordinated control of renal Ca2+ transport proteins by parathyroid hormone.Kidney Int. 2005; 68: 1708-1721Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar Long-term exposure to PTH stimulated transepithelial Ca2+ transport in these epithelial cells, and concomitantly elevated the expression of TRPV5, calbindin-D28K, and NCX1. Blockage of TRPV5 channel activity by ruthenium red eliminated PTH-stimulated transepithelial Ca2+ transport, which was accompanied by a reduction in NCX1 and calbindin-D28K expression. These findings support the hypothesis that the magnitude of the Ca2+ influx through TRPV5 controls the expression of the Ca2+ transport proteins. This implicates an efficient regulation of Ca2+ reabsorption in the kidney where Ca2+ regulates its own transport activity. An important question that remains to be answered is how the flux of Ca2+ through TRPV5 adjusts the expression of the Ca2+ transport proteins. Previous studies have indicated that Ca2+ is important for gene transcription. A Ca2+-responsive element has been identified in the promoter sequence of calbindin-D28K that partly underlies the Purkinje cell-specific expression of calbindin-D28K.18.Arnold D.B. Heintz N. A calcium responsive element that regulates expression of two calcium binding proteins in Purkinje cells.Proc Natl Acad Sci USA. 1997; 94: 8842-8847Crossref PubMed Scopus (67) Google Scholar However, it is not known whether this element is active in the kidney and/or additional intracellular signaling molecules are involved. An established pathway for Ca2+-dependent signaling to the nucleus is via the ubiquitously expressed Ca2+ sensor calmodulin that can stimulate gene expression via distinct pathways. Nuclear calmodulin-dependent kinase IV and the transcription factor CREB (cyclic adenosine 3′,5′ monophosphate response binding protein) are among the calmodulin-regulated proteins that affect gene expression.19.Ashby M.C. Tepikin A.V. Polarized calcium and calmodulin signaling in secretory epithelia.Physiol Rev. 2002; 82: 701-734Crossref PubMed Scopus (100) Google Scholar Besides calmodulin, the Ca2+-binding protein calcineurin/nuclear factor of activated T cells signaling pathway can also stimulate gene expression upon a rise of intracellular Ca2+ and recently this pathway has been shown to be essential for the expression of the sodium-phosphate co-transporter (NaPi) in the kidney.20.Moz Y. Levi R. Lavi-Moshayoff V. et al.Calcineurin Abeta is central to the expression of the renal type II Na/Pi co-transporter gene and to the regulation of renal phosphate transport.J Am Soc Nephrol. 2004; 15: 2972-2980Crossref PubMed Scopus (24) Google Scholar Currently, it is not known whether these pathways are involved in renal TRPV5-mediated Ca2+ signaling. To further identify gene products in the kidney that are regulated by high dietary Ca2+ and/or 1,25(OH)2D3, cDNA microarray analysis was performed on kidneys from high dietary Ca2+ or 1,25(OH)2D3-treated 1α-OHase knockout mice. In this study, 1,25(OH)2D3 induced a significant regulation of ∼1000 genes, whereas dietary Ca2+ supplementation of the 1α-OHase knockout mice revealed ∼2000 controlled genes.3.Hoenderop J.G. Nilius B. Bindels R.J. Calcium absorption across epithelia.Physiol Rev. 2005; 85: 373-422Crossref PubMed Scopus (610) Google Scholar Importantly, Ca2+ transport proteins including NCX1 and calbindin-D28K were among the dietary Ca2+ regulated genes. This confirms previous findings that besides vitamin D, dietary Ca2+ regulates the expression of the renal Ca2+ transport proteins. Furthermore, intracellular signaling molecules, including calmodulin, were identified that might be part of the signaling pathway that underlie the Ca2+ regulated expression in the kidney. Further research is, however, needed to establish a comprehensive molecular mechanism underlying the Ca2+-dependent genomic regulation of the renal Ca2+ transport proteins. Regulation of the renal Ca2+ transport proteins TRPV5, calbindin-D28K, NCX1, and PMCA1b, which determine the net active flux of Ca2+ to the blood compartment, is of physiological importance to maintain the Ca2+ balance. We have presented an overview of the current knowledge concerning the hormonal regulation of renal Ca2+ handling and focused on the mechanism of coordinated control of the renal Ca2+ transport proteins. These findings constitute the mechanism of regulating active Ca2+ reabsorption in the kidney via TRPV5. Once the activity of the gatekeeper TRPV5 is altered, the complete Ca2+ transport machinery will be affected accordingly, as the magnitude of the Ca2+ flux that enters the cell via TRPV5 coordinates the expression of the other Ca2+ transport proteins. The underlying molecular signaling pathway, however, remains to be identified. Future studies like promoter analysis in the Ca2+ transporter genes to identify Ca2+-responsive elements, and experiments focusing on the different Ca2+-dependent signaling pathways will bring further knowledge about the Ca2+-regulated coordinated control of renal Ca2+ transporters. From a clinical point of view, these findings reveal an efficient way to regulate overall renal Ca2+ handling by compounds that specifically stimulate or inhibit the gatekeeper TRPV5." @default.
• W2114781384 created "2016-06-24" @default.
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• W2114781384 date "2006-02-01" @default.
• W2114781384 modified "2023-09-27" @default.
• W2114781384 title "Coordinated control of renal Ca2+ handling" @default.
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• W2114781384 doi "https://doi.org/10.1038/sj.ki.5000169" @default.
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