Post-translational loss of renal trpv5 calcium channel expression, Ca 2+ wasting, and bone loss in experimental colitis

Vijayababu M. Radhakrishnan, Rajalakshmy Ramalingam, Claire B Larmonier, Robert D. Thurston, Daniel Laubitz, Monica T. Midura-Kiela, Rita Marie T McFadden, Makoto Kuro-O, Pawel R Kiela, Fayez K Ghishan

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Abstract

Background & Aims Dysregulated Ca2+ homeostasis likely contributes to the etiology of inflammatory bowel disease-associated loss of bone mineral density. Experimental colitis leads to decreased expression of Klotho, a protein that supports renal Ca2+ reabsorption by stabilizing the transient receptor potential vanilloid 5 (TRPV5) channel on the apical membrane of distal tubule epithelial cells. Methods Colitis was induced in mice via administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS) or transfer of CD4+interleukin-10-/- and CD4+, CD45RBhi T cells. We investigated changes in bone metabolism, renal processing of Ca2+, and expression of TRPV5. Results Mice with colitis had normal serum levels of Ca2+ and parathormone. Computed tomography analysis showed a decreased density of cortical and trabecular bone, and there was biochemical evidence for reduced bone formation and increased bone resorption. Increased fractional urinary excretion of Ca2+ was accompanied by reduced levels of TRPV5 protein in distal convoluted tubules, with a concomitant increase in TRPV5 sialylation. In mouse renal intermedullary collecting duct epithelial (mIMCD3) cells transduced with TRPV5 adenovirus, the inflammatory cytokines tumor necrosis factor, interferon-γ, and interleukin-1β reduced levels of TRPV5 on the cell surface, leading to its degradation. Cytomix induced interaction between TRPV5 and UBR4 (Ubiquitin recoginition 4), an E3 ubiquitin ligase; knockdown of UBR4 with small interfering RNAs prevented cytomix-induced degradation of TRPV5. The effects of cytokines on TRPV5 were not observed in cells stably transfected with membrane-bound Klotho; TRPV5 expression was preserved when colitis was induced with TNBS in transgenic mice that overexpressed Klotho or in mice with T-cell transfer colitis injected with soluble recombinant Klotho. Conclusions After induction of colitis in mice via TNBS administration or T-cell transfer, tumor necrosis factor and interferon-γ reduced the expression and activity of Klotho, which otherwise would protect TRPV5 from hypersialylation and cytokine-induced TRPV5 endocytosis, UBR4-dependent ubiquitination, degradation, and urinary wasting of Ca2+.

Original languageEnglish (US)
Pages (from-to)613-624
Number of pages12
JournalGastroenterology
Volume145
Issue number3
DOIs
StatePublished - Sep 2013

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TRPV Cation Channels
Colitis
Calcium Channels
Kidney
Bone and Bones
Trinitrobenzenesulfonic Acid
Ubiquitin
Cytokines
T-Lymphocytes
Interferons
Tumor Necrosis Factor-alpha
Epithelial Cells
Ubiquitin-Protein Ligases
Membranes
Ubiquitination
Bone Resorption
Endocytosis
Parathyroid Hormone
Interleukin-1
Inflammatory Bowel Diseases

Keywords

  • Mouse Model
  • Osteoporosis
  • UC
  • Ulcerative Colitis

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Post-translational loss of renal trpv5 calcium channel expression, Ca 2+ wasting, and bone loss in experimental colitis. / Radhakrishnan, Vijayababu M.; Ramalingam, Rajalakshmy; Larmonier, Claire B; Thurston, Robert D.; Laubitz, Daniel; Midura-Kiela, Monica T.; McFadden, Rita Marie T; Kuro-O, Makoto; Kiela, Pawel R; Ghishan, Fayez K.

In: Gastroenterology, Vol. 145, No. 3, 09.2013, p. 613-624.

Research output: Contribution to journalArticle

Radhakrishnan, Vijayababu M. ; Ramalingam, Rajalakshmy ; Larmonier, Claire B ; Thurston, Robert D. ; Laubitz, Daniel ; Midura-Kiela, Monica T. ; McFadden, Rita Marie T ; Kuro-O, Makoto ; Kiela, Pawel R ; Ghishan, Fayez K. / Post-translational loss of renal trpv5 calcium channel expression, Ca 2+ wasting, and bone loss in experimental colitis. In: Gastroenterology. 2013 ; Vol. 145, No. 3. pp. 613-624.
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abstract = "Background & Aims Dysregulated Ca2+ homeostasis likely contributes to the etiology of inflammatory bowel disease-associated loss of bone mineral density. Experimental colitis leads to decreased expression of Klotho, a protein that supports renal Ca2+ reabsorption by stabilizing the transient receptor potential vanilloid 5 (TRPV5) channel on the apical membrane of distal tubule epithelial cells. Methods Colitis was induced in mice via administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS) or transfer of CD4+interleukin-10-/- and CD4+, CD45RBhi T cells. We investigated changes in bone metabolism, renal processing of Ca2+, and expression of TRPV5. Results Mice with colitis had normal serum levels of Ca2+ and parathormone. Computed tomography analysis showed a decreased density of cortical and trabecular bone, and there was biochemical evidence for reduced bone formation and increased bone resorption. Increased fractional urinary excretion of Ca2+ was accompanied by reduced levels of TRPV5 protein in distal convoluted tubules, with a concomitant increase in TRPV5 sialylation. In mouse renal intermedullary collecting duct epithelial (mIMCD3) cells transduced with TRPV5 adenovirus, the inflammatory cytokines tumor necrosis factor, interferon-γ, and interleukin-1β reduced levels of TRPV5 on the cell surface, leading to its degradation. Cytomix induced interaction between TRPV5 and UBR4 (Ubiquitin recoginition 4), an E3 ubiquitin ligase; knockdown of UBR4 with small interfering RNAs prevented cytomix-induced degradation of TRPV5. The effects of cytokines on TRPV5 were not observed in cells stably transfected with membrane-bound Klotho; TRPV5 expression was preserved when colitis was induced with TNBS in transgenic mice that overexpressed Klotho or in mice with T-cell transfer colitis injected with soluble recombinant Klotho. Conclusions After induction of colitis in mice via TNBS administration or T-cell transfer, tumor necrosis factor and interferon-γ reduced the expression and activity of Klotho, which otherwise would protect TRPV5 from hypersialylation and cytokine-induced TRPV5 endocytosis, UBR4-dependent ubiquitination, degradation, and urinary wasting of Ca2+.",
keywords = "Mouse Model, Osteoporosis, UC, Ulcerative Colitis",
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AU - Radhakrishnan, Vijayababu M.

AU - Ramalingam, Rajalakshmy

AU - Larmonier, Claire B

AU - Thurston, Robert D.

AU - Laubitz, Daniel

AU - Midura-Kiela, Monica T.

AU - McFadden, Rita Marie T

AU - Kuro-O, Makoto

AU - Kiela, Pawel R

AU - Ghishan, Fayez K

PY - 2013/9

Y1 - 2013/9

N2 - Background & Aims Dysregulated Ca2+ homeostasis likely contributes to the etiology of inflammatory bowel disease-associated loss of bone mineral density. Experimental colitis leads to decreased expression of Klotho, a protein that supports renal Ca2+ reabsorption by stabilizing the transient receptor potential vanilloid 5 (TRPV5) channel on the apical membrane of distal tubule epithelial cells. Methods Colitis was induced in mice via administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS) or transfer of CD4+interleukin-10-/- and CD4+, CD45RBhi T cells. We investigated changes in bone metabolism, renal processing of Ca2+, and expression of TRPV5. Results Mice with colitis had normal serum levels of Ca2+ and parathormone. Computed tomography analysis showed a decreased density of cortical and trabecular bone, and there was biochemical evidence for reduced bone formation and increased bone resorption. Increased fractional urinary excretion of Ca2+ was accompanied by reduced levels of TRPV5 protein in distal convoluted tubules, with a concomitant increase in TRPV5 sialylation. In mouse renal intermedullary collecting duct epithelial (mIMCD3) cells transduced with TRPV5 adenovirus, the inflammatory cytokines tumor necrosis factor, interferon-γ, and interleukin-1β reduced levels of TRPV5 on the cell surface, leading to its degradation. Cytomix induced interaction between TRPV5 and UBR4 (Ubiquitin recoginition 4), an E3 ubiquitin ligase; knockdown of UBR4 with small interfering RNAs prevented cytomix-induced degradation of TRPV5. The effects of cytokines on TRPV5 were not observed in cells stably transfected with membrane-bound Klotho; TRPV5 expression was preserved when colitis was induced with TNBS in transgenic mice that overexpressed Klotho or in mice with T-cell transfer colitis injected with soluble recombinant Klotho. Conclusions After induction of colitis in mice via TNBS administration or T-cell transfer, tumor necrosis factor and interferon-γ reduced the expression and activity of Klotho, which otherwise would protect TRPV5 from hypersialylation and cytokine-induced TRPV5 endocytosis, UBR4-dependent ubiquitination, degradation, and urinary wasting of Ca2+.

AB - Background & Aims Dysregulated Ca2+ homeostasis likely contributes to the etiology of inflammatory bowel disease-associated loss of bone mineral density. Experimental colitis leads to decreased expression of Klotho, a protein that supports renal Ca2+ reabsorption by stabilizing the transient receptor potential vanilloid 5 (TRPV5) channel on the apical membrane of distal tubule epithelial cells. Methods Colitis was induced in mice via administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS) or transfer of CD4+interleukin-10-/- and CD4+, CD45RBhi T cells. We investigated changes in bone metabolism, renal processing of Ca2+, and expression of TRPV5. Results Mice with colitis had normal serum levels of Ca2+ and parathormone. Computed tomography analysis showed a decreased density of cortical and trabecular bone, and there was biochemical evidence for reduced bone formation and increased bone resorption. Increased fractional urinary excretion of Ca2+ was accompanied by reduced levels of TRPV5 protein in distal convoluted tubules, with a concomitant increase in TRPV5 sialylation. In mouse renal intermedullary collecting duct epithelial (mIMCD3) cells transduced with TRPV5 adenovirus, the inflammatory cytokines tumor necrosis factor, interferon-γ, and interleukin-1β reduced levels of TRPV5 on the cell surface, leading to its degradation. Cytomix induced interaction between TRPV5 and UBR4 (Ubiquitin recoginition 4), an E3 ubiquitin ligase; knockdown of UBR4 with small interfering RNAs prevented cytomix-induced degradation of TRPV5. The effects of cytokines on TRPV5 were not observed in cells stably transfected with membrane-bound Klotho; TRPV5 expression was preserved when colitis was induced with TNBS in transgenic mice that overexpressed Klotho or in mice with T-cell transfer colitis injected with soluble recombinant Klotho. Conclusions After induction of colitis in mice via TNBS administration or T-cell transfer, tumor necrosis factor and interferon-γ reduced the expression and activity of Klotho, which otherwise would protect TRPV5 from hypersialylation and cytokine-induced TRPV5 endocytosis, UBR4-dependent ubiquitination, degradation, and urinary wasting of Ca2+.

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KW - Osteoporosis

KW - UC

KW - Ulcerative Colitis

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