Project

Back to overview

Calcium and citrate transporters in renal stone disease

English title Calcium and citrate transporters in renal stone disease
Applicant Hediger Matthias A.
Number 110003
Funding scheme Project funding (Div. I-III)
Research institution Institut für Biochemie und Molekulare Medizin Universität Bern
Institution of higher education University of Berne - BE
Main discipline Biochemistry
Start/End 01.10.2005 - 30.09.2011
Approved amount 1'056'900.00
Show all

All Disciplines (5)

Discipline
Biochemistry
Molecular Biology
Physiology : other topics
Cellular Biology, Cytology
Endocrinology

Keywords (6)

transporter; citrate; epithelial; calcium; transport; kidney stone

Lay Summary (English)

Lead
Lay summary
Calcium is central for many physiological processes in our body. For this reason, the total body calcium homeostasis is under tight control through the coordinated action of intestinal absorption, renal reabsorption and bone resorption. The calcium-selective epithelial ion channels TRPV5 and TRPV6 have been identified and their physiological roles have been revealed: TRPV5 is important in final renal calcium reabsorption, and TRPV6 plays a key role in intestinal calcium absorption (see Hediger and colleagues, Ann Rev Physiol 2008, in press). TRPV5 is expressed in the apical membrane of the distal convoluted tubule of the kidney, where calcium is reabsorbed across the tubule cells, regulated by PTH and 1,25-vitamin D. TRPV6 is expressed in the apical membrane of intestinal epithelial cells where the intestinal calcium is absorbed. The expression of TRPV6 in these intestinal cells is highly regulated by 1,25-vitamin D. Kidney stone disease is a major health problem worldwide, with a lifetime incidence of approximately 10%. Genetic factors appear to be involved since about 40% of these patients have a positive family history. Idiopathic hypercalciuria is the most common abnormality observed in calcium stone formers. There is no report thus far, indicating a general distributing genetic factor, for example mutations and polymorphisms which could be the genetic cause of hypercalciuria.It has previously been reported that polymorphisms in the vitamin D receptor (VDR) gene are associated with a specific form of absorptive hypercalciuria, causing hyper-activation of intestinal calcium absorption, followed by kidney stone disease. In general, these findings indicate that several genes contribute to hypercalciuria. Our laboratory recently demonstrated for the first time that there is an association between hypercalciuria with calcium stone formation and genetic variations of the TRPV6 gene responsible for intestinal calcium absorption. To this end, we investigated the coding regions of the TRPV6 gene in 170 Swiss calcium stone formers. This work was done in collaboration with Prof. Felix Frey (Department of Nephrology and Hypertension, Inselspital Bern). The TRPV6 gene was sequenced in 170 calcium stone forming patients whose calcium homeostasis had been thoroughly studied, 1) on a self-chosen (random) diet, 2) following one week of a low-calcium diet, and 3) after 1 gram oral calcium load at the end of a 12-hour fasting period. We found a haplotype containing three non-synonymous polymorphisms. This haplotype has already been described in a recent genetic study where a positive selection during human evolution was suggested. Our functional analysis of this haplotype indicates that it produces a gain-of-function channel, suggesting that the mutations of this haplotype cause hyper-activation of intestinal calcium absorption, which in turn leads to absorptive hypercalciuria.To investigate the functional significance of the mutated haplotype, we expressed the mutant protein in Xenopus laevis oocytes and found a significantly enhanced calcium uptake activity when tested by 45Ca uptake experiments. These results suggest that a gain of function haplotype in TRPV6 might play a role in calcium stone formation in certain forms of absorptive hypercalciuria. As a follow up, we are going to perform family analyses and evaluate combinations of polymorphisms of the TRPV channel with other transporter-related genes which might be the cause of renal stone formation in members of these families.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Optimization of TRPV6 Calcium Channel Inhibitors Using a 3D Ligand-Based Virtual Screening Method.
Simonin Céline, Awale Mahendra, Brand Michael, van Deursen Ruud, Schwartz Julian, Fine Michael, Kovacs Gergely, Häfliger Pascal, Gyimesi Gergely, Sithampari Abilashan, Charles Roch-Philippe, Hediger Matthias A, Reymond Jean-Louis (2015), Optimization of TRPV6 Calcium Channel Inhibitors Using a 3D Ligand-Based Virtual Screening Method., in Angewandte Chemie (International ed. in English), 54(49), 14748-52.
Chemical inhibitors of the calcium entry channel TRPV6.
Landowski Christopher P, Bolanz Katrin A, Suzuki Yoshiro, Hediger Matthias A (2011), Chemical inhibitors of the calcium entry channel TRPV6., in Pharmaceutical research, 28(2), 322-30.
Heavy metal cations permeate the TRPV6 epithelial cation channel.
Kovacs Gergely, Danko Tamas, Bergeron Marc J, Balazs Bernadett, Suzuki Yoshiro, Zsembery Akos, Hediger Matthias A (2011), Heavy metal cations permeate the TRPV6 epithelial cation channel., in Cell calcium, 49(1), 43-55.
Synthesis, maturation, and trafficking of human Na+-dicarboxylate cotransporter NaDC1 requires the chaperone activity of cyclophilin B.
Bergeron Marc J, Bürzle Marc, Kovacs Gergely, Simonin Alexandre, Hediger Matthias A (2011), Synthesis, maturation, and trafficking of human Na+-dicarboxylate cotransporter NaDC1 requires the chaperone activity of cyclophilin B., in The Journal of biological chemistry, 286(13), 11242-53.
Tamoxifen inhibits TRPV6 activity via estrogen receptor-independent pathways in TRPV6-expressing MCF-7 breast cancer cells.
Bolanz Katrin A, Kovacs Gergely Gy, Landowski Christopher P, Hediger Matthias A (2009), Tamoxifen inhibits TRPV6 activity via estrogen receptor-independent pathways in TRPV6-expressing MCF-7 breast cancer cells., in Molecular cancer research : MCR, 7(12), 2000-10.
Active intestinal calcium transport in the absence of transient receptor potential vanilloid type 6 and calbindin-D9k.
Benn Bryan S, Ajibade Dare, Porta Angela, Dhawan Puneet, Hediger Matthias, Peng Ji-Bin, Jiang Yi, Oh Goo Taeg, Jeung Eui-Bae, Lieben Liesbet, Bouillon Roger, Carmeliet Geert, Christakos Sylvia (2008), Active intestinal calcium transport in the absence of transient receptor potential vanilloid type 6 and calbindin-D9k., in Endocrinology, 149(6), 3196-205.
Calcium channel TRPV6 is involved in murine maternal-fetal calcium transport.
Suzuki Yoshiro, Kovacs Christopher S, Takanaga Hitomi, Peng Ji-Bin, Landowski Christopher P, Hediger Matthias A (2008), Calcium channel TRPV6 is involved in murine maternal-fetal calcium transport., in Journal of bone and mineral research : the official journal of the American Society for Bone and Min, 23(8), 1249-56.
Gain-of-function haplotype in the epithelial calcium channel TRPV6 is a risk factor for renal calcium stone formation.
Suzuki Yoshiro, Pasch Andreas, Bonny Olivier, Mohaupt Markus G, Hediger Matthias A, Frey Felix J (2008), Gain-of-function haplotype in the epithelial calcium channel TRPV6 is a risk factor for renal calcium stone formation., in Human molecular genetics, 17(11), 1613-8.
Inherited epithelial transporter disorders-an overview.
Bergeron M J, Simonin A, Bürzle M, Hediger M A (2008), Inherited epithelial transporter disorders-an overview., in Journal of inherited metabolic disease, 178-187.
Mechanisms and regulation of epithelial Ca2+ absorption in health and disease.
Suzuki Yoshiro, Landowski Christopher P, Hediger Matthias A (2008), Mechanisms and regulation of epithelial Ca2+ absorption in health and disease., in Annual review of physiology, 70, 257-71.
The role of TRPV6 in breast carcinogenesis.
Bolanz Katrin A, Hediger Matthias A, Landowski Christopher P (2008), The role of TRPV6 in breast carcinogenesis., in Molecular cancer therapeutics, 7(2), 271-9.
Marked disturbance of calcium homeostasis in mice with targeted disruption of the Trpv6 calcium channel gene.
Bianco Suzy D C, Peng Ji-Bin, Takanaga Hitomi, Suzuki Yoshiro, Crescenzi Alessandra, Kos Claudine H, Zhuang Liyan, Freeman Michael R, Gouveia Cecilia H A, Wu Jiangping, Luo Hongyu, Mauro Theodora, Brown Edward M, Hediger Matthias A (2007), Marked disturbance of calcium homeostasis in mice with targeted disruption of the Trpv6 calcium channel gene., in Journal of bone and mineral research : the official journal of the American Society for Bone and Min, 22(2), 274-85.
Vitamin D: molecular mechanism of action.
Christakos Sylvia, Dhawan Puneet, Benn Bryan, Porta Angela, Hediger Matthias, Oh Goo T, Jeung Eui-Bae, Zhong Yan, Ajibade Dare, Dhawan Kopal, Joshi Sneha (2007), Vitamin D: molecular mechanism of action., in Annals of the New York Academy of Sciences, 1116, 340-8.
Mutations in the tight-junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement.
Konrad Martin, Schaller Andre, Seelow Dominik, Pandey Amit V, Waldegger Siegfried, Lesslauer Annegret, Vitzthum Helga, Suzuki Yoshiro, Luk John M, Becker Christian, Schlingmann Karl P, Schmid Marcel, Rodriguez-Soriano Juan, Ariceta Gema, Cano Francisco, Enriquez Ricardo, Juppner Harald, Bakkaloglu Sevcan A, Hediger Matthias A, Gallati Sabina, Neuhauss Stephan C F, Nurnberg Peter, Weber Stefanie (2006), Mutations in the tight-junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement., in American journal of human genetics, 79(5), 949-57.
TRPV5 and TRPV6 calcium-selective channels.
Peng J-B Suzuki Y Gyimesi G and Hediger MA, TRPV5 and TRPV6 calcium-selective channels., in Juliusz Ashot Kozak James W. Putney Jr. (ed.), CRC Press, Florida, USA.

Collaboration

Group / person Country
Types of collaboration
Prof. Dr. Christoph Romanin, Johannes Keppler Universität, Linz Austria (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Swiss Transport Mini-Symposium Talk given at a conference Physiology and pathology of epithelial calcium channels and nucleobase transporters 27.11.2009 Kyoto, Japan Hediger Matthias A.;
24th JSSX Annual Meeting Talk given at a conference Membrane transporters and their impact on drug discovery 27.11.2009 Tokyo, Japan Hediger Matthias A.;


Self-organised

Title Date Place

-