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.
Highlights
The calcium-sensing receptor (CaSR) is a dimeric G protein-coupled receptor (GPCR) that plays a central role in calcium homeostasis
To determine the effects of dietary calcium and protein on colitis symptoms, we divided the mice into four groups and fed them the following diets: normal calcium (0.5%) and protein, low calcium, high calcium, and high protein (Table 1)
Our findings revealed that dietary calcium and protein differentially affect key parameters in the dextran sulphate sodium (DSS) colitis mouse model
Summary
The calcium-sensing receptor (CaSR) is a dimeric G protein-coupled receptor (GPCR) that plays a central role in calcium homeostasis. The CaSR fine-tunes numerous signaling pathways downstream of Gi , GQ/11 , G12/13 and β-arrestin in a ligand- and tissue-dependent manner [5,6,7,8,9,10] This is evident in the diversity of the physiological processes that the CaSR regulates, spanning calcitropic and non-calcitropic tissues, i.e., those not directly involved in calcium homeostasis. These include proliferation, differentiation, hormone secretion and excitability to name but a few [1]. The CaSR may potentially be a therapeutic target for toxin-mediated diarrhea and intestinal inflammation
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