Disease relevance of AQP2

• Lack of functional AQP2 is seen in primary forms of diabetes insipidus, and reduced expression and targeting are seen in several diseases associated with urinary concentrating defects such as acquired nephrogenic diabetes insipidus, postobstructive polyuria, as well as acute and chronic renal failure [1].
• In contrast, in conditions with water retention such as severe congestive heart failure, pregnancy, and syndrome of inappropriate antidiuretic hormone secretion, both AQP2 expression levels and apical plasma membrane targetting are increased, suggesting a role for AQP2 in the development of water retention [1].
• This concerns inherited forms of nephrogenic diabetes insipidus and several, much more common acquired types of nephrogenic diabetes insipidus where AQP2 expression and/or targeting are affected [2].
• Disregulation or malfunctioning of AQP2 can lead to severe diseases such as nephrogenic diabetes insipidus, congestive heart failure, liver cirrhosis and pre-eclampsia [3].
• CONCLUSIONS: Although the single effect of therapeutic dose of lithium was weak, it effectively and safely compensated for the therapeutic limitations of a low dose of AVP V(2) receptor antagonist for SIADH by reducing AQP2 expression [4].

Psychiatry related information on AQP2

• The expression of aquaporin-2 (AQP2) in the immature kidney is low; however, under conditions of water deprivation and after stimulation with DDAVP, it rises to adult levels [5].
• Lithium, a drug for bipolar disorders, has been known to cause nephrogenic diabetes insipidus by reducing kidney-specific apical water channel, aquaporin 2 (AQP2) expression in the collecting ducts [4].
• Prior knowledge of AVPR2 or AQP2 mutations in NDI families and perinatal mutation testing is of direct clinical value because early diagnosis and treatment can avert the physical and mental retardation associated with repeated episodes of dehydration [6].
• This study clearly demonstrates that urinary calcium levels modulate AQP2 excretion and is likely to be useful for treatment of children with enuresis [7].
• Urinary aquaporin-2 excretion during early human development [8].

High impact information on AQP2

• Body water balance is tightly regulated by vasopressin, and multiple studies now have underscored the essential roles of AQP2 in this [1].
• Vasopressin regulates acutely the water permeability of the kidney collecting duct by trafficking of AQP2 from intracellular vesicles to the apical plasma membrane [1].
• The long-term adaptational changes in body water balance are controlled in part by regulated changes in AQP2 and AQP3 expression levels [1].
• We measured the urinary excretion of aquaporin-2 and its response to vasopressin in 11 normal subjects and 9 patients with central or nephrogenic diabetes insipidus [9].
• In the five normal subjects tested, the mean (+/- SE) urinary excretion of aquaporin-2 was 11.2 +/- 2.2 pmol per milligram of creatinine after a period of dehydration, and it decreased to 3.9 +/- 1.9 pmol per milligram of creatinine (P = 0.03) during the second hour after a period of hydration [9].

Chemical compound and disease context of AQP2

• Defective AQP2 trafficking causes nephrogenic diabetes insipidus, a condition characterized by the kidney inability to produce concentrated urine because of the insensitivity of the distal nephron to vasopressin [10].
• Water deprivation or arginine vasotocin upregulates aquaporin-2 (AQP2) expression in apical and subapical regions of medullary collecting duct (CD) cells of Coturnix coturnix quail (q) kidneys [11].
• A 24-hour urinary excretion of AQP-2 was significantly elevated in patients with CHF (median, 25.7 nmol/mol creatinine) compared to healthy controls (15.7 nmol/mol creatinine) and those with liver cirrhosis (17 nmol/mol creatinine) [12].
• Aldosterone increases urine production and decreases apical AQP2 expression in rats with diabetes insipidus [13].
• Down-regulation of Na+ transporters and AQP2 is responsible for acyclovir-induced polyuria and hypophosphatemia [14].

Biological context of AQP2

• AQP2 vesicles and the IMCD apical membrane contain homologs of vesicle-targeting and signal transduction proteins found in neurons [15].
• Although missense mutations in AQP1 and AQP2 proteins are known to result in recessive traits in vivo and in vitro, when E134G or T138R are co-expressed with wild-type AQP0 protein, the mutant proteins exhibit dominant negative behaviour [16].
• Along with T126M, mutations H122S, N124S, and A125T were introduced to preserve the consensus sequence for N-linked glycosylation found in human AQP2 [17].
• Using oocytes, externally applied TEA blocked AQP1/AQP2/AQP4 with IC50 values of 1.4, 6.2, and 9.8 microM, respectively [18].
• The acquired form of NDI is much more common than the congenital form, is almost always less severe, and is associated with downregulation of AQP2 [19].

Anatomical context of AQP2

• AVP-elicited trafficking of AQP2 with the apical membrane occurs via a specialized population of vesicles that resemble synaptic vesicles in neurons [15].
• Expression studies in Xenopus oocytes showed that the missense AQP2 proteins are nonfunctional [20].
• Previous studies have demonstrated that AQP2 vesicles constitute a distinct intracellular compartment partially overlapping with early endosomes [21].
• In this report, we performed in vitro experiments using the renal epithelial cell line, Madin-Darby canine kidney (MDCK) cells, stably expressing AQP2 (MDCK-hAQP2) [21].
• In polarized MDCK-hAQP2 cells, AQP2 vesicles were localized in the subapical recycling compartment and distinct from the Golgi apparatus, trans-Golgi network, lysosome, and early endosome in the nonstimulated state [21].

Associations of AQP2 with chemical compounds

• AQP2 is exclusively expressed in the principal cells of the connecting tubule and collecting duct and is the predominant vasopressin-regulated water channel [1].
• Together, the results suggest that the decrease in AVP-stimulated osmotic water permeability results, at least in part, in the decrease in AQP2 protein [22].
• Similarly AQP2 mutant proteins are trapped intracellularly and cannot be expressed at the luminal membrane [19].
• Patients who have congenital NDI and bear mutations in the AVPR2 or AQP2 genes have a "pure" NDI phenotype with loss of water but normal conservation of sodium, potassium, chloride, and calcium [23].
• Then, AQP2 moved from EEA1-positive endosomes to the subapical AQP2-storage compartment, which is sensitive to wortmannin and LY294002 [21].

Physical interactions of AQP2

• AQP2 is redistributed to the apical membrane of collecting duct cells through activation of a cAMP signaling cascade initiated by the binding of vasopressin to its V2-receptor [10].
• AVP binds to V2-receptors and induces the translocation of aquaporin-2 water channels (AQP-2) into the apical plasma membrane of principal cells [24].

Co-localisations of AQP2

• Washout of forskolin induced retrieval of AQP2 into the cytoplasm, and AQP2 was transiently colocalized with EEA1-positive endosomes [21].
• TRPC3 and -C6 colocalized with aquaporin-2, but not with the Na(+)/Ca(2+) exchanger or peanut lectin [25].

Regulatory relationships of AQP2

• Short-term control of water permeability occurs via vesicular trafficking of AQP2 and long-term control through changes in the abundance of AQP2 and AQP3 water channels [10].
• Soluble N-ethylmaleimide sensitive fusion factor attachment protein receptors (SNARE) and actin cytoskeleton organization regulated by small GTPase of the Rho family were also proved to be essential for AQP2 trafficking [10].
• Thus, non-osmotic release of AVP in CHF upregulates AQP2 water channels, enhances water reabsorption and causes hyponatremia [26].
• This AQP2 upregulation can be entirely suppressed by V2 receptor AVP antagonists paralleling the correction of the hyponatremia [26].
• Emerging data suggest that TonEBP plays a key role in the urinary concentrating mechanism by stimulating the UT-A urea transporters and possibly AQP2 water channel [27].

Other interactions of AQP2

• Selective V2-receptor vasopressin antagonism decreases urinary aquaporin-2 excretion in patients with chronic heart failure [28].
• AQP1 is expressed in apical and basolateral membranes of proximal tubules and descending limbs of Henle, AQP2 predominantly in apical membranes of principal and inner medullary collecting duct cells and AQP3 in basolateral membranes of kidney collecting duct cells [29].
• Aquaporin-2 (AQP-2), a water channel located on the apical membrane of collecting duct cells, regulates water reabsorption under the control of vasopressin (AVP) [28].
• Data for functional involvement of the SNARE vesicle-associated membrane protein 2 in AQP2 targeting has recently been provided [10].
• AQP0, AQP2, and AQP9 were not found in any corneas [30].

Analytical, diagnostic and therapeutic context of AQP2

• Northern blot analysis showed up-regulated AQP2-T126M transcripts of identical size to wild-type AQP2 [17].
• Here we present the crystallization of recombinantly expressed human AQP2 into two-dimensional protein-lipid arrays and their structural characterization by atomic force microscopy and electron crystallography [3].
• AVP and AQP2 concentrations were measured by radioimmunoassay [31].
• Protein expression of AQP2 was examined by western blotting at the end of the observation period [4].
• RT-PCR screen of multiple rat tissues identified AQP2 transcripts in the cochlea, testis and kidney and an absence of tissue-specific splice variants [32].

References