Department of Clinical and Translational Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, USA, United States.
Inflamm Bowel Dis. 2021 Oct 20;27(11):1804-1812. doi: 10.1093/ibd/izab093.
In the small intestine, Na:H (NHE3) and Cl:HCO3 (DRA or PAT1) exchangers present in the brush border membrane (BBM) of absorptive villus cells are primarily responsible for the coupled absorption of NaCl, the malabsorption of which causes diarrhea, a common symptom of inflammatory bowel disease (IBD). Inducible nitric oxide (iNO), a known mediator of inflammation, is increased in the mucosa of the chronically inflamed IBD intestine. An SAMP1/YitFc (SAMP1) mouse, a spontaneous model of chronic ileitis very similar to human IBD, was used to study alterations in NaCl absorption. The SAMP1 and control AKR mice were treated with I-N(6)-(1-Iminoethyl)-lysine (L-NIL) to inhibit iNO production, and DRA/PAT1 and NHE3 activities and protein expression were studied. Though Na:H exchange activity was unaffected, Cl:HCO3 activity was significantly decreased in SAMP1 mice due to a reduction in its affinity for Cl, which was reversed by L-NIL treatment. Though DRA and PAT1 expressions were unchanged in all experimental conditions, phosphorylation studies indicated that DRA, not PAT1, is affected in SAMP1. Moreover, the altered phosphorylation levels of DRA was restored by L-NIL treatment. Inducible NO mediates the inhibition of coupled NaCl absorption by decreasing Cl:HCO3 but not Na:H exchange. Specifically, Cl:HCO3 exchanger DRA but not PAT1 is regulated at the level of its phosphorylation by iNO in the chronically inflamed intestine.
在小肠中，刷状缘膜（BBM）中存在的 Na:H（NHE3）和 Cl:HCO3（DRA 或 PAT1）交换器主要负责 NaCl 的偶联吸收，其吸收不良导致腹泻，这是炎症性肠病（IBD）的常见症状。诱导型一氧化氮（iNO）是炎症的已知介质，在慢性炎症的 IBD 肠黏膜中增加。SAMP1/YitFc（SAMP1）小鼠是一种慢性回肠炎的自发性模型，非常类似于人类 IBD，用于研究 NaCl 吸收的改变。SAMP1 和对照 AKR 小鼠用 I-N（6）-（1-亚氨基乙基）赖氨酸（L-NIL）治疗以抑制 iNO 产生，并研究 DRA/PAT1 和 NHE3 活性和蛋白表达。尽管 Na:H 交换活性不受影响，但由于 Cl 亲和力降低，SAMP1 小鼠的 Cl:HCO3 活性显著降低，L-NIL 治疗可逆转这种降低。尽管 DRA 和 PAT1 的表达在所有实验条件下均未改变，但磷酸化研究表明 DRA 而不是 PAT1 受到影响。此外，L-NIL 治疗可恢复 DRA 的改变磷酸化水平。诱导型 NO 通过降低 Cl:HCO3 来介导偶联 NaCl 吸收的抑制，但不影响 Na:H 交换。具体而言，Cl:HCO3 交换器 DRA 而不是 PAT1 通过慢性炎症肠中的 iNO 调节其磷酸化水平。
