Nutritional and Pharmacological Targeting of the Calcium-Sensing Receptor Influences Chemically Induced Colitis in Mice.

Abstract

The calcium-sensing receptor (CaSR) is the main regulator of extracellular Ca2+ homeostasis. It has diverse functions in different tissues, including the intestines. Intestine-specific knockout of the CaSR renders mice more susceptible to dextran sulphate sodium (DSS)-induced colitis. To test our hypothesis that the CaSR reduces intestinal inflammation, we assessed the effects of nutritional and pharmacological agonists of the CaSR in a colitis model. We treated female Balb/C mice with dietary calcium and protein (nutritional agonists of the CaSR) or pharmacological CaSR modulators (the agonists cinacalcet and GSK3004774, and the antagonist NPS-2143; 10 mg/kg), then induced colitis with DSS. The high-protein diet had a strong pro-inflammatory effect-it shortened the colons (5.3 ± 0.1 cm vs. 6.1 ± 0.2 cm normal diet, p < 0.05), lowered mucin expression and upregulated pro-inflammatory cytokines, such as interferon-γ, (4.2-fold, p < 0.05) compared with the normal diet. Cinacalcet reduced mucin expression, which coincided with an increase in tumor necrosis factor-α (4.4-fold, p < 0.05) and IL-6 (4.9-fold, p < 0.05) in the plasma, compared with vehicle. The CaSR antagonist, NPS-2143, significantly reduced the cumulative inflammation score compared with the vehicle control (35.3 ± 19.1 vs. 21.9 ± 14.3 area under the curve, p < 0.05) and reduced infiltration of inflammatory cells. While dietary modulation of the CaSR had no beneficial effects, pharmacological inhibition of the CaSR may have the potential of a novel add-on therapy in the treatment of inflammatory bowel diseases.

• Authors: Taha Elajnaf, Luca Iamartino, Ildiko Mesteri, Christian Müller, Marcella Bassetto, Teresa Manhardt, Sabina Baumgartner-Parzer, Enikö Kallay, Martin Schepelmann
• Journal: Nutrients (Nutrients) Vol. 11 Issue 12 (Dec 16 2019) ISSN: 2072-6643 [Electronic] Switzerland
• PMID: 31888253 (Publication Type: Journal Article)

Chemical References

• CASR protein, mouse
• Calcium, Dietary
• Cytokines
• Dietary Proteins
• N-(2-hydroxy-3-(2-cyano-3-chlorophenoxy)propyl)-1,1-dimethyl-2-(2-nephthyl)ethylamine
• Naphthalenes
• Receptors, Calcium-Sensing
• Dextran Sulfate

Topics

• Animals
• Calcium, Dietary (pharmacology)
• Colitis (chemically induced, metabolism)
• Colon (metabolism)
• Cytokines (metabolism)
• Dextran Sulfate
• Diet, High-Protein (adverse effects)
• Dietary Proteins (pharmacology)
• Female
• Inflammation
• Intestinal Mucosa (metabolism)
• Mice
• Mice, Inbred BALB C
• Naphthalenes (administration & dosage)
• Receptors, Calcium-Sensing (agonists)