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  1. Article ; Online: The role of transient receptor potential channels in kidney disease.

    Woudenberg-Vrenken, Titia E / Bindels, René J M / Hoenderop, Joost G J

    Nature reviews. Nephrology

    2009  Volume 5, Issue 8, Page(s) 441–449

    Abstract: The transient receptor potential (TRP) superfamily consists, in mammals, of six protein subfamilies, TRPC, TRPM, TRPV, TRPA, TRPML and TRPP. TRPs are cation channels involved in many physiological processes and in the pathogenesis of various disorders. ... ...

    Abstract The transient receptor potential (TRP) superfamily consists, in mammals, of six protein subfamilies, TRPC, TRPM, TRPV, TRPA, TRPML and TRPP. TRPs are cation channels involved in many physiological processes and in the pathogenesis of various disorders. In the kidney, TRP channels are expressed along the nephron, and a role for some of these channels in renal function has been proposed. TRPC3 is thought to facilitate calcium ion influx into the principal cells of the collecting duct in response to vasopressin. TRPM3 and TRPV4 might be osmosensors, whereas the TRPP1/TRPP2 complex could function as a mechanosensor in the cilia of renal epithelial cells. A number of kidney diseases have also been linked to dysfunctional activity of TRPs. TRPC6 dysfunction has been associated with the onset of focal segmental glomerosclerosis; TRPP2 dysfunction is linked to autosomal-dominant polycystic kidney disease, TRPM6 mutations underlie hypomagnesemia with secondary hypocalcemia, and TRPV1 dysfunction is implicated in renal hypertension. A link between TRPC1 dysfunction and diabetic nephropathy has also been suggested in an animal model. Animal studies have implicated a role for TRPV5 in idiopathic hypercalciuria and vitamin D-dependent rickets, although these observations have not been confirmed in patients. This Review focuses on the role of renal TRP channels in health and disease.
    MeSH term(s) Animals ; Calcium/metabolism ; Humans ; Kidney Diseases/genetics ; Kidney Diseases/metabolism ; Kidney Diseases/physiopathology ; Magnesium/metabolism ; Mutation ; Signal Transduction ; Transient Receptor Potential Channels/genetics ; Transient Receptor Potential Channels/metabolism ; Transient Receptor Potential Channels/physiology
    Chemical Substances Transient Receptor Potential Channels ; Magnesium (I38ZP9992A) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2009-06-23
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2490366-8
    ISSN 1759-507X ; 1759-5061
    ISSN (online) 1759-507X
    ISSN 1759-5061
    DOI 10.1038/nrneph.2009.100
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  2. Article ; Online: Metformin protects rat hepatocytes against bile acid-induced apoptosis.

    Woudenberg-Vrenken, Titia E / Conde de la Rosa, Laura / Buist-Homan, Manon / Faber, Klaas Nico / Moshage, Han

    PloS one

    2013  Volume 8, Issue 8, Page(s) e71773

    Abstract: Background: Metformin is used in the treatment of Diabetes Mellitus type II and improves liver function in patients with non-alcoholic fatty liver disease (NAFLD). Metformin activates AMP-activated protein kinase (AMPK), the cellular energy sensor that ... ...

    Abstract Background: Metformin is used in the treatment of Diabetes Mellitus type II and improves liver function in patients with non-alcoholic fatty liver disease (NAFLD). Metformin activates AMP-activated protein kinase (AMPK), the cellular energy sensor that is sensitive to changes in the AMP/ATP-ratio. AMPK is an inhibitor of mammalian target of rapamycin (mTOR). Both AMPK and mTOR are able to modulate cell death.
    Aim: To evaluate the effects of metformin on hepatocyte cell death.
    Methods: Apoptotic cell death was induced in primary rat hepatocytes using either the bile acid glycochenodeoxycholic acid (GCDCA) or TNFα in combination with actinomycin D (actD). AMPK, mTOR and phosphoinositide-3 kinase (PI3K)/Akt were inhibited using pharmacological inhibitors. Apoptosis and necrosis were quantified by caspase activation, acridine orange staining and Sytox green staining respectively.
    Results: Metformin dose-dependently reduces GCDCA-induced apoptosis, even when added 2 hours after GCDCA, without increasing necrotic cell death. Metformin does not protect against TNFα/ActD-induced apoptosis. The protective effect of metformin is dependent on an intact PI3-kinase/Akt pathway, but does not require AMPK/mTOR-signaling. Metformin does not inhibit NF-κB activation.
    Conclusion: Metformin protects against bile acid-induced apoptosis and could be considered in the treatment of chronic liver diseases accompanied by inflammation.
    MeSH term(s) AMP-Activated Protein Kinases/metabolism ; Animals ; Apoptosis/drug effects ; Bile Acids and Salts/metabolism ; Bile Acids and Salts/pharmacology ; Caspase 3/metabolism ; Cell Membrane/metabolism ; Dose-Response Relationship, Drug ; Glycochenodeoxycholic Acid/metabolism ; Hepatocytes/drug effects ; Hepatocytes/metabolism ; Hepatocytes/pathology ; Hypoglycemic Agents/pharmacology ; Male ; Metformin/pharmacology ; NF-kappa B/metabolism ; Necrosis/drug therapy ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism
    Chemical Substances Bile Acids and Salts ; Hypoglycemic Agents ; NF-kappa B ; Glycochenodeoxycholic Acid (640-79-9) ; Metformin (9100L32L2N) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; AMP-Activated Protein Kinases (EC 2.7.11.31) ; Caspase 3 (EC 3.4.22.-)
    Language English
    Publishing date 2013-08-12
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0071773
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  3. Article ; Online: Functional TRPV6 channels are crucial for transepithelial Ca2+ absorption.

    Woudenberg-Vrenken, Titia E / Lameris, Anke L / Weißgerber, Petra / Olausson, Jenny / Flockerzi, Veit / Bindels, René J M / Freichel, Marc / Hoenderop, Joost G J

    American journal of physiology. Gastrointestinal and liver physiology

    2012  Volume 303, Issue 7, Page(s) G879–85

    Abstract: TRPV6 is considered the primary protein responsible for transcellular Ca2+ absorption. In vitro studies demonstrate that a negatively charged amino acid (D) within the putative pore region of mouse TRPV6 (position 541) is critical for Ca2+ permeation of ... ...

    Abstract TRPV6 is considered the primary protein responsible for transcellular Ca2+ absorption. In vitro studies demonstrate that a negatively charged amino acid (D) within the putative pore region of mouse TRPV6 (position 541) is critical for Ca2+ permeation of the channel. To elucidate the role of TRPV6 in transepithelial Ca2+ transport in vivo, we functionally analyzed a TRPV6D541A/D541A knockin mouse model. After weaning, mice were fed a regular (1% wt/wt) or Ca2+-deficient (0.02% wt/wt) diet and housed in metabolic cages. Blood was sampled for Ca2+ measurements, and the expression of Ca2+ transport proteins was analyzed in kidney and duodenum. Intestinal 45Ca2+ uptake was measured in vivo by an absorption assay. Challenging the mice with the Ca2+-deficient diet resulted in hypocalcemia in wild-type and TRPV6D541A/D541A mice. On a low-Ca2+ diet both mouse strains displayed increased expression of intestinal TRPV6, calbindin-D(9K), and renal TRPV5. TRPV6D541A/D541A mice showed significantly impaired intestinal Ca2+ uptake compared with wild-type mice, and duodenal TRPV5 expression was increased in TRPV6D541A/D541A mice. On a normal diet, serum Ca2+ concentrations normalized in both mouse strains. Under these conditions, intestinal Ca2+ uptake was similar, and the expression levels of renal and intestinal Ca2+ transport proteins were not affected. We demonstrate that TRPV6D541A/D541A mice exhibit impaired transcellular Ca2+ absorption. Duodenal TRPV5 expression was increased in TRPV6D541A/D541A mice, albeit insufficient to correct for the diminished Ca2+ absorption. Under normal conditions, when passive Ca2+ transport is predominant, no differences between wild-type and TRPV6D541A/D541A mice were observed. Our results demonstrate a specific role for TRPV6 in transepithelial Ca2+ absorption.
    MeSH term(s) Animals ; Calbindins ; Calcium/blood ; Calcium/pharmacokinetics ; Calcium Channels/metabolism ; Calcium-Binding Proteins/metabolism ; Diet/adverse effects ; Diet/methods ; Hypocalcemia/metabolism ; Intestinal Absorption/physiology ; Intestinal Mucosa/physiology ; Kidney/metabolism ; Mice ; Mice, Knockout ; S100 Calcium Binding Protein G/metabolism ; TRPV Cation Channels/genetics ; TRPV Cation Channels/metabolism ; Transcytosis
    Chemical Substances Calbindins ; Calcium Channels ; Calcium-Binding Proteins ; S100 Calcium Binding Protein G ; TRPV Cation Channels ; TRPV6 channel ; Trpv5 protein, mouse ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2012-10
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 603840-2
    ISSN 1522-1547 ; 0193-1857
    ISSN (online) 1522-1547
    ISSN 0193-1857
    DOI 10.1152/ajpgi.00089.2012
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  4. Article ; Online: Transient receptor potential melastatin 6 knockout mice are lethal whereas heterozygous deletion results in mild hypomagnesemia.

    Woudenberg-Vrenken, Titia E / Sukinta, Arjaree / van der Kemp, Annemiete W / Bindels, René J M / Hoenderop, Joost G J

    Nephron. Physiology

    2011  Volume 117, Issue 2, Page(s) p11–9

    Abstract: Background: Hypomagnesemia with secondary hypocalcemia is due to disturbed renal and intestinal magnesium (Mg(2+)) (re)absorption. The underlying defect is a mutation in the transient receptor potential melastatin type 6 (TRPM6), a Mg(2+)-permeable ion ... ...

    Abstract Background: Hypomagnesemia with secondary hypocalcemia is due to disturbed renal and intestinal magnesium (Mg(2+)) (re)absorption. The underlying defect is a mutation in the transient receptor potential melastatin type 6 (TRPM6), a Mg(2+)-permeable ion channel expressed in the kidney and intestine. Our aim was to characterize homozygous (-/-) and heterozygous (+/-) TRPM6 knockout mice with respect to Mg(2+) homeostasis.
    Methods: TRPM6(+/-) mice were bred on a normal (0.19% wt/wt Mg(2+)) and high (0.48% wt/wt Mg(2+)) Mg(2+) diet. In the offspring, 24-hour urinary Mg(2+) and calcium excretion as well as serum concentrations of both were determined. TRPM6 mRNA expression in the kidney and colon was measured.
    Results: On the regular diet, 30% of the offspring were TRPM6 wild-type ((+/+)), 70% were TRPM6(+/-), and none were TRPM6(-/-). The genotypic distribution of the litters remained the same on the 0.48% Mg(2+) diet. In TRPM6(+/-) mice on both diets, serum Mg(2+) levels were significantly lower, and renal and intestinal TRPM6 mRNA expression was reduced. Urinary Mg(2+) excretion was unaffected.
    Conclusions: Homozygous TRPM6 deletion is embryonic lethal in mice. Heterozygous deletion of TRPM6 results in a mild hypomagnesemia. The Mg(2+)-enriched diet could not compensate for either embryonic lethality or hypomagnesemia caused by TRPM6 deficiency.
    MeSH term(s) Animals ; Calcium/urine ; Feces/chemistry ; Female ; Gene Deletion ; Gene Expression/physiology ; Genes, Lethal ; Genotype ; Heterozygote ; Magnesium/blood ; Magnesium/urine ; Magnesium Deficiency/blood ; Magnesium Deficiency/genetics ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Severity of Illness Index ; TRPM Cation Channels/genetics ; TRPM Cation Channels/metabolism
    Chemical Substances TRPM Cation Channels ; Trpm6 protein, mouse ; Magnesium (I38ZP9992A) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2011
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 207121-6
    ISSN 1660-2137 ; 1423-0186 ; 2235-3186 ; 1660-8151 ; 0028-2766
    ISSN (online) 1660-2137 ; 1423-0186 ; 2235-3186
    ISSN 1660-8151 ; 0028-2766
    DOI 10.1159/000320580
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  5. Article ; Online: Metformin protects rat hepatocytes against bile acid-induced apoptosis.

    Titia E Woudenberg-Vrenken / Laura Conde de la Rosa / Manon Buist-Homan / Klaas Nico Faber / Han Moshage

    PLoS ONE, Vol 8, Iss 8, p e

    2013  Volume 71773

    Abstract: BACKGROUND: Metformin is used in the treatment of Diabetes Mellitus type II and improves liver function in patients with non-alcoholic fatty liver disease (NAFLD). Metformin activates AMP-activated protein kinase (AMPK), the cellular energy sensor that ... ...

    Abstract BACKGROUND: Metformin is used in the treatment of Diabetes Mellitus type II and improves liver function in patients with non-alcoholic fatty liver disease (NAFLD). Metformin activates AMP-activated protein kinase (AMPK), the cellular energy sensor that is sensitive to changes in the AMP/ATP-ratio. AMPK is an inhibitor of mammalian target of rapamycin (mTOR). Both AMPK and mTOR are able to modulate cell death. AIM: To evaluate the effects of metformin on hepatocyte cell death. METHODS: Apoptotic cell death was induced in primary rat hepatocytes using either the bile acid glycochenodeoxycholic acid (GCDCA) or TNFα in combination with actinomycin D (actD). AMPK, mTOR and phosphoinositide-3 kinase (PI3K)/Akt were inhibited using pharmacological inhibitors. Apoptosis and necrosis were quantified by caspase activation, acridine orange staining and Sytox green staining respectively. RESULTS: Metformin dose-dependently reduces GCDCA-induced apoptosis, even when added 2 hours after GCDCA, without increasing necrotic cell death. Metformin does not protect against TNFα/ActD-induced apoptosis. The protective effect of metformin is dependent on an intact PI3-kinase/Akt pathway, but does not require AMPK/mTOR-signaling. Metformin does not inhibit NF-κB activation. CONCLUSION: Metformin protects against bile acid-induced apoptosis and could be considered in the treatment of chronic liver diseases accompanied by inflammation.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
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  6. Article ; Online: Effective siRNA delivery to inflamed primary vascular endothelial cells by anti-E-selectin and anti-VCAM-1 PEGylated SAINT-based lipoplexes.

    Leus, Niek G J / Talman, Eduard G / Ramana, Pranov / Kowalski, Piotr S / Woudenberg-Vrenken, Titia E / Ruiters, Marcel H J / Molema, Grietje / Kamps, Jan A A M

    International journal of pharmaceutics

    2014  Volume 459, Issue 1-2, Page(s) 40–50

    Abstract: ... of antibodies to the distal end of PEG (so-called antibody-SAINTPEGargs), resulted in anti-E-selectin- and anti ...

    Abstract The endothelium represents an attractive therapeutic target due to its pivotal role in many diseases including chronic inflammation and cancer. Small interfering RNAs (siRNAs) specifically interfere with the expression of target genes and are considered an important new class of therapeutics. However, due to their size and charge, siRNAs do not spontaneously enter unperturbed endothelial cells (EC). To overcome this problem, we developed novel lipoplexes for siRNA delivery that are based on the cationic amphiphilic lipid SAINT-C18. Antibodies recognizing disease induced cell adhesion molecules were employed to create cell specificity resulting in so-called antibody-SAINTargs. To improve particle stability, antibody-SAINTargs were further optimized for EC-specific siRNA-mediated gene silencing by addition of polyethylene glycol (PEG). Although PEGylated antibody-SAINTargs maintained specificity, they lost their siRNA delivery capacity. Coupling of antibodies to the distal end of PEG (so-called antibody-SAINTPEGargs), resulted in anti-E-selectin- and anti-vascular cell adhesion molecule (VCAM)-1-SAINTPEGarg that preserved their antigen recognition and their capability to specifically deliver siRNA into inflammation-activated primary endothelial cells. The enhanced uptake of siRNA by antibody-SAINTPEGargs was followed by improved silencing of the target gene VE-cadherin, demonstrating that antibody-SAINTPEGargs were capable of functionally delivering siRNA into primary endothelial cells originating from different vascular beds. In conclusion, the newly developed, physicochemically stable, and EC-specific siRNA carrying antibody-SAINTPEGargs selectively down-regulate target genes in primary endothelial cells that are generally difficult to transfect.
    MeSH term(s) Capillaries/cytology ; Cells, Cultured ; Drug Delivery Systems ; E-Selectin/chemistry ; Electrochemistry ; Endothelial Cells/pathology ; Endothelium, Vascular/pathology ; Flow Cytometry ; Gene Expression ; Gene Transfer Techniques ; Human Umbilical Vein Endothelial Cells/metabolism ; Human Umbilical Vein Endothelial Cells/pathology ; Humans ; Inflammation/pathology ; Lipids/chemistry ; Particle Size ; Polyethylene Glycols/chemistry ; Pyridinium Compounds/chemistry ; RNA, Small Interfering/administration & dosage ; Real-Time Polymerase Chain Reaction ; Transfection ; Vascular Cell Adhesion Molecule-1/chemistry
    Chemical Substances 1-methyl-4-(9-dioleyl)methylpyridinium ; E-Selectin ; Lipids ; Pyridinium Compounds ; RNA, Small Interfering ; Vascular Cell Adhesion Molecule-1 ; Polyethylene Glycols (30IQX730WE)
    Language English
    Publishing date 2014-01-01
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 428962-6
    ISSN 1873-3476 ; 0378-5173
    ISSN (online) 1873-3476
    ISSN 0378-5173
    DOI 10.1016/j.ijpharm.2013.11.008
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    Zs.A 1409: Show issues Location:
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  7. Article ; Online: Anti-oxidants do not prevent bile acid-induced cell death in rat hepatocytes.

    Woudenberg-Vrenken, Titia E / Buist-Homan, Manon / Conde de la Rosa, Laura / Faber, Klaas Nico / Moshage, Han

    Liver international : official journal of the International Association for the Study of the Liver

    2010  Volume 30, Issue 10, Page(s) 1511–1521

    Abstract: Background: Bile acids, reactive oxygen species (ROS) and inflammatory cytokines are crucial regulators of cell death in acute and chronic liver diseases. The contribution of each factor to hepatocyte death, either apoptosis or necrosis, has not been ... ...

    Abstract Background: Bile acids, reactive oxygen species (ROS) and inflammatory cytokines are crucial regulators of cell death in acute and chronic liver diseases. The contribution of each factor to hepatocyte death, either apoptosis or necrosis, has not been clarified as yet. It has been suggested that the generation of oxidative stress by bile acids contributes to hepatocyte death during cholestasis and bile acid toxicity, although the beneficial role of ROS prevention in bile acid-mediated cell death is not fully understood.
    Aim: Study the effects of anti-oxidants in bile acid-induced cell death in vitro.
    Methods: Primary rat hepatocytes were exposed to the bile acids glycochenodeoxycholic acid (GCDCA) or taurolithocholic acid-3 sulphate in the absence or presence of ROS scavengers or anti-oxidants. Haeme oxygenase (HO)-1 mRNA levels were analysed by quantitative polymerase chain reaction. Apoptosis was quantified by acridine orange staining and caspase-3 activity assay. Necrosis was detected by Sytox green staining.
    Results: Anti-oxidants do not attenuate bile acid-induced cell death. Furthermore, bile acid exposure does not enhance the mRNA expression of the oxidative stress-responsive gene HO-1. The Src-kinase inhibitor, SU6656, does reduce GCDCA-induced apoptosis and necrosis.
    Conclusions: In hepatocytes, bile acid-induced toxicity is not prevented by scavengers of oxidative stress. The beneficial effects observed in patients might be because of the contribution of ROS and cytokines rather than bile acid-mediated oxidative stress. However, the use of specific Src kinase inhibitors might be a useful tool to prevent bile acid-induced injury in liver diseases.
    MeSH term(s) Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Caspase 3/metabolism ; Cells, Cultured ; Cytoprotection ; Glycochenodeoxycholic Acid/metabolism ; Heme Oxygenase (Decyclizing)/genetics ; Heme Oxygenase (Decyclizing)/metabolism ; Hepatocytes/drug effects ; Hepatocytes/metabolism ; Hepatocytes/pathology ; Male ; NADPH Oxidases/antagonists & inhibitors ; NADPH Oxidases/metabolism ; Necrosis ; Oxidative Stress/drug effects ; Protein Kinase Inhibitors/pharmacology ; RNA, Messenger/metabolism ; Rats ; Rats, Wistar ; Rats, Zucker ; Reactive Oxygen Species/metabolism ; Taurolithocholic Acid/analogs & derivatives ; Taurolithocholic Acid/metabolism ; src-Family Kinases/antagonists & inhibitors ; src-Family Kinases/metabolism
    Chemical Substances Antioxidants ; Protein Kinase Inhibitors ; RNA, Messenger ; Reactive Oxygen Species ; taurolithocholic acid 3-sulfate (15324-65-9) ; Taurolithocholic Acid (516-90-5) ; Glycochenodeoxycholic Acid (640-79-9) ; Heme Oxygenase (Decyclizing) (EC 1.14.14.18) ; Hmox1 protein, rat (EC 1.14.14.18) ; NADPH Oxidases (EC 1.6.3.-) ; src-Family Kinases (EC 2.7.10.2) ; Casp3 protein, rat (EC 3.4.22.-) ; Caspase 3 (EC 3.4.22.-)
    Language English
    Publishing date 2010-11
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2102783-3
    ISSN 1478-3231 ; 1478-3223
    ISSN (online) 1478-3231
    ISSN 1478-3223
    DOI 10.1111/j.1478-3231.2010.02325.x
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  8. Article ; Online: Characterization of vitamin D-deficient klotho(-/-) mice: do increased levels of serum 1,25(OH)2D3 cause disturbed calcium and phosphate homeostasis in klotho(-/-) mice?

    Woudenberg-Vrenken, Titia E / van der Eerden, Bram C J / van der Kemp, AnneMiete W C M / van Leeuwen, Johannes P T M / Bindels, René J M / Hoenderop, Joost G J

    Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association

    2012  Volume 27, Issue 11, Page(s) 4061–4068

    Abstract: Background: Klotho(-/-) mice display disturbed Ca(2+) and vitamin D homeostasis. Renal cytochrome p450 27b1 (Cyp27b1), the enzyme that catalyzes the hydrolysis to 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), is increased in klotho(-/-) mice, and a 1,25( ...

    Abstract Background: Klotho(-/-) mice display disturbed Ca(2+) and vitamin D homeostasis. Renal cytochrome p450 27b1 (Cyp27b1), the enzyme that catalyzes the hydrolysis to 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), is increased in klotho(-/-) mice, and a 1,25(OH)(2)D(3)-deficient diet partially normalized Ca(2+) homeostasis in these klotho(-/-) mice. The aim of the present study was to further delineate the interplay between 1,25(OH)(2)D(3) and klotho and their relative contribution to the Ca(2+) homeostasis of klotho(-/-) mice.
    Methods: Double-klotho(-/-)/Cyp27b1(-/-) mice were generated and mice aged 8-12 weeks were housed in metabolic cages to collect 24-h urine. Blood samples were taken and the animals were sacrificed, and the kidney and duodenum tissues were sampled for RNA extraction. The bone was fixed in 10% v/v formalin and analysed by microcomputed tomography (μCT) scans.
    Results: Klotho(-/-)/Cyp27b1(-/-) mice, like Cyp27b1(-/-) mice, displayed significantly decreased serum total calcium concentrations compared with wild-type mice (1.44 ± 0.03 and 2.25 ± 0.02 mM) along with normal urinary total calcium excretion. Hyperphosphataemia of klotho(-/-) mice normalized to wild-type levels in klotho(-/-)/Cyp27b1(-/-) mice. The mRNA levels of duodenal transient receptor potential vanilloid subtype 6 (TRPV6) and calcium-binding protein-D(9K), and renal calbindin-D(28K) and NCX1 were significantly reduced in the double knockouts compared with wild-type or klotho(-/-) mice. Elevated TRPV5 protein levels in klotho(-/-) mice normalized to wild type in klotho(-/-)/Cyp27b1(-/-) mice, but were decreased in Cyp27b1(-/-) mice. μCT scans showed that klotho(-/-)/Cyp27b1(-/-) mice, as Cyp27b1(-/-) mice, display significant bone hypomineralization and severely decreased bone mass. Klotho(-/-) mice show a reduced bone mass and increased trabecular numbers.
    Conclusions: Klotho(-/-)/Cyp27b1(-/-) mice resemble Cyp27b1(-/-) mice. Since 1,25(OH)(2)D(3) is absent in these mice, our results imply that Ca(2+) homeostasis in klotho(-/-) mice is affected by their excessive 1,25(OH)(2)D(3) levels.
    MeSH term(s) 25-Hydroxyvitamin D3 1-alpha-Hydroxylase/metabolism ; Animals ; Blotting, Western ; Bone and Bones/metabolism ; Calcium/blood ; Calcium/urine ; Duodenum/metabolism ; Glucuronidase/genetics ; Glucuronidase/metabolism ; Homeostasis ; Immunohistochemistry ; Mice ; Mice, Knockout ; Phosphates/blood ; Phosphates/urine ; Real-Time Polymerase Chain Reaction ; TRPV Cation Channels/metabolism ; Vitamin D/analogs & derivatives ; Vitamin D/blood ; Vitamin D Deficiency/blood ; Vitamin D Deficiency/urine
    Chemical Substances Phosphates ; TRPV Cation Channels ; dihydroxy-vitamin D3 ; Vitamin D (1406-16-2) ; 25-Hydroxyvitamin D3 1-alpha-Hydroxylase (EC 1.14.13.13) ; Glucuronidase (EC 3.2.1.31) ; klotho protein (EC 3.2.1.31) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2012-11
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 90594-x
    ISSN 1460-2385 ; 0931-0509
    ISSN (online) 1460-2385
    ISSN 0931-0509
    DOI 10.1093/ndt/gfs177
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Caveolin-1 is enriched in the peroxisomal membrane of rat hepatocytes.

    Woudenberg, Jannes / Rembacz, Krzysztof P / van den Heuvel, Fiona A J / Woudenberg-Vrenken, Titia E / Buist-Homan, Manon / Geuken, Mariska / Hoekstra, Mark / Deelman, Leo E / Enrich, Carlos / Henning, Rob H / Moshage, Han / Faber, Klaas Nico

    Hepatology (Baltimore, Md.)

    2010  Volume 51, Issue 5, Page(s) 1744–1753

    Abstract: Unlabelled: Caveolae are a subtype of cholesterol-enriched lipid microdomains/rafts that are routinely detected as vesicles pinching off from the plasma membrane. Caveolin-1 is an essential component of caveolae. Hepatic caveolin-1 plays an important ... ...

    Abstract Unlabelled: Caveolae are a subtype of cholesterol-enriched lipid microdomains/rafts that are routinely detected as vesicles pinching off from the plasma membrane. Caveolin-1 is an essential component of caveolae. Hepatic caveolin-1 plays an important role in liver regeneration and lipid metabolism. Expression of caveolin-1 in hepatocytes is relatively low, and it has been suggested to also reside at other subcellular locations than the plasma membrane. Recently, we found that the peroxisomal membrane contains lipid microdomains. Like caveolin-1, hepatic peroxisomes are involved in lipid metabolism. Here, we analyzed the subcellular location of caveolin-1 in rat hepatocytes. The subcellular location of rat hepatocyte caveolin-1 was analyzed by cell fractionation procedures, immunofluorescence, and immuno-electron microscopy. Green fluorescent protein (GFP)-tagged caveolin-1 was expressed in rat hepatocytes. Lipid rafts were characterized after Triton X-100 or Lubrol WX extraction of purified peroxisomes. Fenofibric acid-dependent regulation of caveolin-1 was analyzed. Peroxisome biogenesis was studied in rat hepatocytes after RNA interference-mediated silencing of caveolin-1 and caveolin-1 knockout mice. Cell fractionation and microscopic analyses reveal that caveolin-1 colocalizes with peroxisomal marker proteins (catalase, the 70 kDa peroxisomal membrane protein PMP70, the adrenoleukodystrophy protein ALDP, Pex14p, and the bile acid-coenzyme A:amino acid N-acyltransferase BAAT) in rat hepatocytes. Artificially expressed GFP-caveolin-1 accumulated in catalase-positive organelles. Peroxisomal caveolin-1 is associated with detergent-resistant microdomains. Caveolin-1 expression is strongly repressed by the peroxisome proliferator-activated receptor-alpha agonist fenofibric acid. Targeting of peroxisomal matrix proteins and peroxisome number and shape were not altered in rat hepatocytes with 70%-80% reduced caveolin-1 levels and in livers of caveolin-1 knockout mice.
    Conclusion: Caveolin-1 is enriched in peroxisomes of hepatocytes. Caveolin-1 is not required for peroxisome biogenesis, but this unique subcellular location may determine its important role in hepatocyte proliferation and lipid metabolism.
    MeSH term(s) ATP-Binding Cassette Transporters/metabolism ; Acyltransferases/metabolism ; Animals ; Caveolin 1/metabolism ; Fenofibrate/analogs & derivatives ; Fenofibrate/pharmacology ; Hepatocytes/metabolism ; Male ; Membrane Microdomains/metabolism ; Membrane Proteins/metabolism ; Mice ; Mice, Knockout ; Peroxins ; Peroxisomes/drug effects ; Peroxisomes/metabolism ; Rats ; Rats, Wistar ; Subcellular Fractions/metabolism
    Chemical Substances Abcd3 protein, rat ; Caveolin 1 ; Membrane Proteins ; Peroxins ; Pex11a protein, rat ; fenofibric acid (BGF9MN2HU1) ; Acyltransferases (EC 2.3.-) ; bile acid-CoA amino acid N-acyltransferase (EC 2.3.1.-) ; Fenofibrate (U202363UOS)
    Language English
    Publishing date 2010-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 604603-4
    ISSN 1527-3350 ; 0270-9139
    ISSN (online) 1527-3350
    ISSN 0270-9139
    DOI 10.1002/hep.23460
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Transient Receptor Potential Melastatin 6 Knockout Mice Are Lethal whereas Heterozygous Deletion Results in Mild Hypomagnesemia

    Woudenberg-Vrenken, Titia E. / Sukinta, Arjaree / van der Kemp, Annemiete W. / Bindels, René J.M. / Hoenderop, Joost G.J.

    Nephron Physiology

    2011  Volume 117, Issue 2, Page(s) p11–p19

    Abstract: Background: Hypomagnesemia with secondary hypocalcemia is due to disturbed renal and intestinal magnesium (Mg2+) (re)absorption. The underlying defect is a mutation in the transient receptor potential melastatin type 6 (TRPM6), a Mg2+-permeable ion ... ...

    Abstract Background: Hypomagnesemia with secondary hypocalcemia is due to disturbed renal and intestinal magnesium (Mg2+) (re)absorption. The underlying defect is a mutation in the transient receptor potential melastatin type 6 (TRPM6), a Mg2+-permeable ion channel expressed in the kidney and intestine. Our aim was to characterize homozygous (-/-) and heterozygous (+/-) TRPM6 knockout mice with respect to Mg2+ homeostasis. Methods: TRPM6+/- mice were bred on a normal (0.19% wt/wt Mg2+) and high (0.48% wt/wt Mg2+) Mg2+ diet. In the offspring, 24-hour urinary Mg2+ and calcium excretion as well as serum concentrations of both were determined. TRPM6 mRNA expression in the kidney and colon was measured. Results: On the regular diet, 30% of the offspring were TRPM6 wild-type (+/+), 70% were TRPM6+/-, and none were TRPM6-/-. The genotypic distribution of the litters remained the same on the 0.48% Mg2+ diet. In TRPM6+/- mice on both diets, serum Mg2+ levels were significantly lower, and renal and intestinal TRPM6 mRNA expression was reduced. Urinary Mg2+ excretion was unaffected. Conclusions: Homozygous TRPM6 deletion is embryonic lethal in mice. Heterozygous deletion of TRPM6 results in a mild hypomagnesemia. The Mg2+-enriched diet could not compensate for either embryonic lethality or hypomagnesemia caused by TRPM6 deficiency.
    Keywords Hypomagnesemia ; Knockout mouse ; Magnesium (re)absorption ; Transient receptor potential melastatin 6 ; Transient receptor potential melastatin 7
    Language English
    Publisher S. Karger AG
    Publishing place Basel
    Publishing country Switzerland
    Document type Article ; Online
    ZDB-ID 207121-6
    ISSN 1660-2137 ; 1423-0186 ; 0028-2766 ; 1660-8151 ; 1660-2137 ; 0028-2766 ; 1660-8151
    ISSN (online) 1660-2137 ; 1423-0186
    ISSN 1660-2137 ; 0028-2766 ; 1660-8151
    DOI 10.1159/000320580
    Database Karger publisher's database

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