1.A.8.8.8
Vasopressin-sensitive aquaporin-2 (Aqp2) in the apical membrane of the renal collecting duct (Fenton et al., 2008).  Controls cell volume and thereby influences cell proliferation (Di Giusto et al. 2012).  It  plays a key role in concentrating urine. Water reabsorption is regulated by AQP2 trafficking between intracellular storage vesicles and the apical membrane. This process is tightly controlled by the pituitary hormone arginine vasopressin, and defective trafficking results in nephrogenic diabetes insipidus (NDI).  The crystal structure of Aqp2 has been solved to 2.75 Å (Frick et al. 2014).  In terrestrial vertebrates, AQP2 function is generally regulated by arginine-vasopressin to accomplish key functions in osmoregulation such as the maintenance of body water homeostasis by a cyclic AMP-independent mechanism (Olesen and Fenton 2017; Martos-Sitcha et al. 2015). AQP2 is expressed in the anterior vaginal wall and fibroblasts, and regulates the expression level of collagen I/III i, suggesting that AQP2 is associated with the pathogenesis of stress urinary incontinence through collagen metabolism during ECM remodeling (Zhang et al. 2017). As in humans, the chicken ortholog, Aqp2, is found only in the kidney (Ramírez-Lorca et al. 2006).  AQP2 is critical in regulating urine concentrating ability. The expression and function of AQP2 are regulated by a series of transcriptional factors and post-transcriptional phosphorylation, ubiquitination, and glycosylation (He and Yang 2019). Mutation or functional deficiency of AQP2 leads to severe nephrogenic diabetes insipidus, and inhibition of various aquaporins leads to many water-related diseases such as, edema, cardiac arrest, and stroke. Maroli et al. 2019 reported on the molecular mechanisms of mycotoxin (citrinin, ochratoxin-A, and T-2 mycotoxin) inhibition of AQP2 and arginine vasopressin receptor 2 (AVPR2). Aquaporin-2 mutations cause Nephrogenic diabetes insipidus (Li et al. 2021). Meniere's disease is affected by dexamethasone which is a direct modulator of AQP2. The molecular mechanisms involved in dexamethasone binding to and its regulatory action upon AQP2 function have been described (Mom et al. 2022). Interaction of cortisol with aquaporin-2 modulates its water permeability (Mom et al. 2023). In the kidney collecting duct, arginine vasopressin-dependent trafficking of AQP2 fine-tunes reabsorption of water from pre-urine, allowing precise regulation of the final urine volume. Point mutations in the gene for AQP2 disturbs this process and leads to nephrogenic diabetes insipidus (NDI), wherein patients void large volumes of hypo-osmotic urine. In recessive NDI, mutants of AQP2 are retained in the endoplasmic reticulum due to misfolding. The structures allow interpretation of these results (Hagströmer et al. 2023). Differential regulation of autophagy on urine-concentrating capability occurs through modulating renal AQP2 expression (Xu et al. 2023). Aqp2 interacts with Ezrin (see 8.A.25.1.1 for a detailed description). In vivo treatment with calcilytic of Ca2+-sensitive receptors (CaSR ) knock-in mice ameliorates the renal phenotype reversing downregulation of the vasopressin-AQP2 pathway (Ranieri et al. 2024).  The posttranslational modification ubiquitylation is a key regulator of AQP2 abundance and plasma membrane localization. Cullin-RING E3 ligases play a vital role in mediating some of the effects of vasopressin to increase AQP2 abundance and plasma membrane accumulation (Murali et al. 2024).  There is a correlation between chronic subdural hematoma volume and serum AQP2 concentration, highlighting aquaporins' potential as clinical biomarkers (Czyżewski et al. 2024).