Characterization of intestine-specific TRPM6 knockout C57BL/6 J mice: effects of short-term omeprazole treatment

Abstract

The transient receptor potential melastatin type 6 (TRPM6) is a divalent cation channel pivotal for gatekeeping Mg 2+ balance. Disturbance in Mg 2+ balance has been associated with the chronic use of proton pump inhibitors (PPIs) such as omeprazole. In this study, we investigated if TRPM6 plays a role in mediating the effects of short-term (4 days) omeprazole treatment on intestinal Mg 2+ malabsorption using intestine-specific TRPM6 knockout ( Vill1 -TRPM6 −/− ) mice. To do this, forty-eight adult male C57BL/6 J mice (50% TRPM6 fl/fl and 50% Vill1 -TRPM6 −/− ) were characterized, and the distal colon of these mice was subjected to RNA sequencing. Moreover, these mice were exposed to 20 mg/kg bodyweight omeprazole or placebo for 4 days. Vill1 -TRPM6 −/− mice had a significantly lower 25 Mg 2+ absorption compared to control TRPM6 fl/fl mice, accompanied by lower Mg 2+ serum levels, and urinary Mg 2+ excretion. Furthermore, renal Slc41a3 , Trpm6 , and Trpm7 gene expressions were higher in these animals, indicating a compensatory mechanism via the kidney. RNA sequencing of the distal colon revealed a downregulation of the Mn 2+ transporter Slc30a10 . However, no changes in Mn 2+ serum, urine, and feces levels were observed. Moreover, 4 days omeprazole treatment did not affect Mg 2+ homeostasis as no changes in serum 25 Mg 2+ and total Mg 2+ were seen. In conclusion, we demonstrate here for the first time that Vill1 -TRPM6 −/− mice have a lower Mg 2+ absorption in the intestines. Moreover, short-term omeprazole treatment does not alter Mg 2+ absorption in both Vill1 -TRPM6 −/− and TRPM6 fl/fl mice. This suggests that TRPM6-mediated Mg 2+ absorption in the intestines is not affected by short-term PPI administration.

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