Centrone Mariangela, D'Agostino Mariagrazia, Ranieri Marianna, Mola Maria Grazia, Faviana Pinuccia, Lippolis Piero Vincenzo, Silvestris Domenico Alessandro, Venneri Maria, Di Mise Annarita, Valenti Giovanna, Tamma Grazia
Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari Aldo Moro, Bari, Italy.
Department of Surgical, Medical, Molecular Pathology, and Critical Area, University of Pisa, Pisa, Italy.
Front Cell Dev Biol. 2022 Jul 8;10:919438. doi: 10.3389/fcell.2022.919438. eCollection 2022.
Vasopressin (AVP) plays a key function in controlling body water and salt balance through the activation of the vasopressin receptors V1aR and V2R. Abnormal secretion of AVP can cause the syndrome of inappropriate antidiuresis that leads to hyponatremia, which is an electrolyte disorder often observed in the elderly hospitalized and oncologic patients. Beyond kidneys, the colonic epithelium modulates water and salt homeostasis. The water channel AQP3, expressed in villus epithelial cells is implicated in water absorption across human colonic surface cells. Here, the action of dDAVP, a stable vasopressin analog, was evaluated on the AQP3 expression and function using human colon HCT8 cells as an experimental model. Confocal and Western Blotting analysis revealed that HCT8 cells express both V1aR and V2R. Long-term (72 h) treatment with dDAVP reduced glycerol uptake and cell viability. These effects were prevented by SR49059, a synthetic antagonist of V1aR, but not by tolvaptan, a specific V2R antagonist. Of note, the SR49059 action was impaired by DFP00173, a selective inhibitor of AQP3. Interestingly, compared to the normal colonic mucosa, in the colon of patients with adenocarcinoma, the expression of V1aR was significantly decreased. These findings were confirmed by gene expression analysis with RNA-Seq data. Overall, data suggest that dDAVP, through the V1aR dependent pathway, reduces AQP3 mediated glycerol uptake, a process that is reversed in adenocarcinoma, suggesting that the AVP-dependent AQP3 pathway may represent a novel target in colon diseases associated with abnormal cell growth.
血管加压素（AVP）通过激活血管加压素受体V1aR和V2R在控制机体水盐平衡中发挥关键作用。AVP分泌异常可导致抗利尿激素分泌不当综合征，进而引起低钠血症，这是老年住院患者和肿瘤患者中常见的一种电解质紊乱。除肾脏外，结肠上皮也参与调节水盐稳态。在绒毛上皮细胞中表达的水通道蛋白AQP3与人类结肠表面细胞的水吸收有关。在此，以人结肠HCT8细胞为实验模型，评估了稳定的血管加压素类似物dDAVP对AQP3表达和功能的作用。共聚焦和蛋白质印迹分析显示，HCT8细胞同时表达V1aR和V2R。dDAVP长期（72小时）处理可降低甘油摄取和细胞活力。V1aR的合成拮抗剂SR49059可预防这些作用，但V2R特异性拮抗剂托伐普坦则不能。值得注意的是，AQP3的选择性抑制剂DFP00173削弱了SR49059的作用。有趣的是，与正常结肠黏膜相比，在腺癌患者的结肠中，V1aR的表达显著降低。RNA测序数据的基因表达分析证实了这些发现。总体而言，数据表明dDAVP通过V1aR依赖性途径降低AQP3介导的甘油摄取，这一过程在腺癌中会逆转提示AVP依赖性AQP3途径可能是与异常细胞生长相关的结肠疾病的新靶点。
