Adella Anastasia, Gommers Lisanne M M, Bos Caro, Leermakers Pieter A, de Baaij Jeroen H F, Hoenderop Joost G J
Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Pflugers Arch. 2025 Jan;477(1):99-109. doi: 10.1007/s00424-024-03017-9. Epub 2024 Sep 13.
The transient receptor potential melastatin type 6 (TRPM6) is a divalent cation channel pivotal for gatekeeping Mg balance. Disturbance in Mg 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 malabsorption using intestine-specific TRPM6 knockout (Vill1-TRPM6) mice. To do this, forty-eight adult male C57BL/6 J mice (50% TRPM6 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 Mg absorption compared to control TRPM6 mice, accompanied by lower Mg serum levels, and urinary Mg 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 transporter Slc30a10. However, no changes in Mn serum, urine, and feces levels were observed. Moreover, 4 days omeprazole treatment did not affect Mg homeostasis as no changes in serum Mg and total Mg were seen. In conclusion, we demonstrate here for the first time that Vill1-TRPM6 mice have a lower Mg absorption in the intestines. Moreover, short-term omeprazole treatment does not alter Mg absorption in both Vill1-TRPM6 and TRPM6 mice. This suggests that TRPM6-mediated Mg absorption in the intestines is not affected by short-term PPI administration.
瞬时受体电位褪黑素6型（TRPM6）是一种对维持镁平衡至关重要的二价阳离子通道。镁平衡紊乱与长期使用质子泵抑制剂（PPI）如奥美拉唑有关。在本研究中，我们使用肠道特异性TRPM6基因敲除（Vill1-TRPM6）小鼠，研究TRPM6是否在介导短期（4天）奥美拉唑治疗对肠道镁吸收不良的影响中发挥作用。为此，对48只成年雄性C57BL/6 J小鼠（50%为TRPM6小鼠，50%为Vill1-TRPM6小鼠）进行了特征分析，并对这些小鼠的远端结肠进行了RNA测序。此外，这些小鼠接受20 mg/kg体重的奥美拉唑或安慰剂处理4天。与对照TRPM6小鼠相比，Vill1-TRPM6小鼠的镁吸收显著降低，同时血清镁水平和尿镁排泄也较低。此外，这些动物的肾脏中Slc41a3、Trpm6和Trpm7基因表达较高，表明存在通过肾脏的代偿机制。远端结肠的RNA测序显示锰转运蛋白Slc30a10下调。然而，未观察到血清、尿液和粪便中锰水平的变化。此外，4天的奥美拉唑治疗未影响镁稳态，因为血清镁和总镁未见变化。总之，我们首次在此证明Vill1-TRPM6小鼠肠道镁吸收较低。此外，短期奥美拉唑治疗不会改变Vill1-TRPM6和TRPM6小鼠的镁吸收。这表明肠道中TRPM6介导的镁吸收不受短期PPI给药的影响。
