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We studied the anti-tumorigenic effect of melatonin in diethylstilbestrol (DES)-treated anterior pituitaries in rats. Twenty-one female Wistar rats were randomly allocated into three groups: vehicle control rats, DES-treated rats, and DES-treated rats co-administrated with melatonin beginning at week 13. At the end of 16 weeks, rats were weighed and decapitated for morphological studies, including an H+E staining-based score evaluation in regard to cell proliferation, angiogenesis, immunostaining for VEGF, MMP-9, and AQP-1, and electron microscopy. Compared with vehicle, long-term treatment of DES significantly reduced rat body weight and increased H+E score, both of which were counteracted by melatonin. Administration of melatonin also reduced the expression of VEGF and MMP-9, although no changes were detected in AQP-1 expression. In rats cotreated with melatonin, the RER loosened and accumulated more secretion granules. We thus concluded that melatonin can modulate the effects of DES on the rat anterior pituitary by downregulating expression of VEGF and MMP-9 and suppressing the release of secretion granules, suggesting a therapeutic potential in estrogen-induced pituitary malfunctions. [ABSTRACT FROM AUTHOR]

Aquaporin-1 (AQP1) is a water channel protein expressed in endothelial and epithelial cells of many tissues, including the vasculature, where it serves to increase water permeability of the cell membrane. Prior studies have also reported that AQP1 plays a central role in tumor angiogenesis by promoting endothelial cell migration. To investigate whether AQP1 might also influence vascular angiogenesis in ischemic myocardium, the expression level of AQP1 for 21 days post myocardial infarction in rabbit hearts was observed. Aquaporin-1 mRNA and protein levels in day 3, and peaked on day 7 post surgery. This correlated well with the pattern of neovascularization and increased water content of infarct border tissue, and suggested that AQP1 may be involved in myocardial angiogenesis in response to ischemia injury. These AQP1-induced changes were tempered by acetazolamide, a carbonic anhydrase inhibitor, which acted by downregulating AQP1 expression. Acetazolamide treatment did not significantly affect the expression of vascular endothelial growth factor in the tissues studied. Our findings indicate a novel role for AQP1 in postnatal angiogenesis, which has implications in diverse pathophysiological conditions including wound healing, tumor metastasis, and organ regeneration. [ABSTRACT FROM AUTHOR]

Aquaporins (AQPs) are key regulators of water channels across the cell cytoplasm. Little is known about AQP localization and changes in the hepatic microvascular system. This study aimed to clarify the localization of AQP-1 in the microvessels in normal and cirrhotic rat liver. To establish a rat cirrhosis model, thioacetamide (TAA) was injected for 24 weeks. AQP-1 in liver specimens was examined by immunohistochemistry (IHC), Western blotting, and immunoelectron microscopy (IEM). IHC revealed that AQP-1 was localized in hepatic sinusoids, especially on the liver sinusoidal endothelial cells (LSECs), predominantly in zone 1 in control rats, whereas AQP-1 immunoreactivity was increased on LSECs in central portions of regenerative nodules in cirrhotic rats, and was expressed especially strongly on the outer side of the duplicated liver cell cords. IEM demonstrated that, in control livers, AQP-1 was mainly expressed on the plasma membrane of LSECs in zone 1. In cirrhotic livers, many immunogold particles showing the presence of AQP-1 were seen on the LSECs in central portions of regenerative nodules, and the number was significantly greater than that in zone 3 of control liver. Protein levels of AQP-1 examined by Western blot were almost the same in the cirrhotic liver and control liver. AQP-1 immunoreactivities were aberrantly expressed on LSECs in central portions of regenerative nodule (CPRN) of cirrhotic liver, which may be associated with capillarization of LSECs and remodeling in this region. [ABSTRACT FROM AUTHOR]

Abstract: A significant long-term side effect of radiation therapy for head and neck cancers is xerostomia, a dry mouth, due to salivary gland damage. Despite continuing efforts to eliminate this problem, many patients continue to suffer. This brief review describes our efforts to develop a gene transfer approach, employing the aquaporin-1 cDNA, to treat patients with existing radiation-induced salivary hypofunction. A Phase I/II clinical trial, using a recombinant adenoviral vector to mediate gene transfer, is currently underway. [Copyright &y& Elsevier]

Abstract: We investigated the expression and localization of aquaporin-1 (AQP-1) in hepatitis B virus (HBV)-associated cirrhotic human liver tissues. The expression of AQP-1 at the protein and mRNA levels was analyzed by immunohistochemistry, quantitative real-time polymerase chain reaction (qPCR) and Western blotting in normal and HBV-associated cirrhotic human liver tissues. The correlation with the expression of CK19, CK7 and AQP-1 was also compared. AQP-1 staining was strongly and uniformly positive in mature bile ducts, isolated hepatic progenitor cells (HPCs) and ductular reactions. Scattered intermediate hepatocyte-like cells expressed AQP-1, which are often intimately associated with CK7 positive hepatocytes. However, the number of AQP-1+ intermediate hepatocyte-like cells was lower than that of CK7+ cells, and such positivity was rarely seen on stains for CK19. When compared with normal liver tissues, AQP-1 was overexpressed at both the mRNA and protein levels in the cirrhotic liver tissues. AQP-1 was overexpressed in the cirrhotic liver tissues. AQP-1, similar to CK19, might be a more specific and more sensitive marker than CK7 for the identification of HPCs. [Copyright &y& Elsevier]

Abstract: We examined the expression of aquaporin (AQP)-1 in monolayers of the rat gastric epithelial cell line RGM1 and investigated the roles AQP1 plays in the epithelial restitution during wound healing. A round wound of constant size was produced in the center of a confluent cell monolayer using a rotating silicon tip. The RGM1 cells expressed AQP1 mRNA. Hg2+ (HgCl2), an inhibitor of AQPs, suppressed cell migration during wound repair in a concentration-dependent manner. Likewise, cell migration was also impaired in cells in which AQP1 was knocked down by RNA interference, resulting in a marked delay of wound healing. The AQP1 knockdown RGM1 cells showed a decrease in the formation of membrane protrusions (lamellipodia) at the leading edge of the wound as compared with control RGM1 cells. These results suggest for the first time that AQP1 plays a crucial role in gastric epithelial cell migration during wound healing. [Copyright &y& Elsevier]

Acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), remain leading factors for morbidity and mortality in critically ill patients. A significant aspect of ALI and ARDS is impaired alveolar fluid clearance (AFC). Improvements in therapies for these types of respiratory illnesses will require an understanding of the mechanisms that control AFC. The present study was designed to determine whether the administration of dobutamine decreases pulmonary edema and stimulates AFC in a rat model of lipopolysaccharide-induced lung injury. Adult male Sprague–Dawley rats were randomly divided into three groups: control, lipopolysaccharide, and lipopolysaccharide + dobutamine. The effect of dobutamine on AFC and the expression of aquaporin-1 and aquaporin-5 were examined. Lipopolysaccharide administration results in significant lung injury with impaired AFC, while dobutamine improves alveolar fluid reabsorption with elevation of aquaporin-1 and aquaporin-5. Our study indicates that dobutamine may enhance alveolar fluid reabsorption by increasing the expression of aquaporin-1 and aquaporin-5. [ABSTRACT FROM AUTHOR]

Abstract: Aquaporin-4 (AQP4) has been implicated in cytotoxic brain edema resulting from water intoxication, brain ischemia or meningitis. AQP4 inhibitors suitable for clinical use would thus be expected to help protect against brain edema. Here, we report the effect of inhibitors on water conduction by AQP4 and AQP1 reconstituted into liposomes. Acetazolamide (AZA), an inhibitor of sulfonamide carbonic anhydrase (CA), reversibly inhibits water permeation through AQP4, but not through AQP1. Methazolamide (MZA), another sulfonamide CA inhibitor similar in chemical structure to AZA, shows no significant effect on water conduction by AQP4 or AQP1. Our results thus demonstrate that AZA acts as a reversible inhibitor for AQP4-mediated water conduction and indicate that AZA is specific, at least to some degree, for AQP4. AZA may thus serve as a lead compound for the development of AQP4-specific inhibitors for clinical applications. [Copyright &y& Elsevier]

The transcription factor Pax2 is essential for kidney development in mice, and overexpression of Pax2 in chick embryos leads to ectopic formation of nephric structures. We have generated embryonic stem (ES) cell lines that repress Pax2 expression in a tetracycline-dependent manner. In the absence of tetracycline, embryoid bodies derived from these cell lines expressed Pax2 and subsequently integrin α8 and aquaporin-1 ( Aqp1), both of which are possibly involved in kidney development. Considering the slow induction kinetics, our data suggest that Pax2 and additional factors that are induced in embryoid bodies synergistically regulate the two targets. The ES cell lines with inducible Pax2 expression will also be useful for dissecting genetic cascades functioning in a variety of organ development. [ABSTRACT FROM AUTHOR]

Aquaporins are membrane water channel proteins that are expressed in the epithelium and endothelium. Their primary function is to control the flow of water in the membranes of the cells. In this study, we investigated whether there is increased expression of aquaporin-1 in the tunica vaginalis of hydrocele patients in childhood that do not regress spontaneously an whether it has an effect on the etiology of hydrocele. Boys who were diagnosed with hydrocele and scheduled for surgery were included and formed the hydrocele group. Boys in the same age range who underwent surgery for inguinal hernia or undescended testicles were included as a control group. Aquaporin-1 expression was evaluated by immunohistochemical examination of capillaries in tissue samples taken from the tunica vaginalis during the operation. Aquaporin-1-positive vessels were counted by selecting 5 unrelated areas with the highest vascular density, and the average number of vessels was calculated for each case. A total of 48 male patients were included in the study. Of these, 27 constituted the hydrocele group (mean age 3.51 ± 2.59 years), and 21 constituted the control group (inguinal hernia, n = 17; undescended testicle, n = 4) (mean age 3.95 ± 3.80 years). The mean ages of both groups were statistically similar (p = 0.32). The mean numbers of aquaporin-1-positive vessels at the capillaries in the tunica vaginalis of the patients were 20.74 ± 7.10 in hydrocele group and 17.23 ± 4.07 in the control group. The expression of aquaporin-1 in the hydrocele group was significantly higher (p = 0.037). It was shown that aquaporin-1 expression was higher in adult cases with hydrocele. Also an increase in aquaporin-1 expression was detected in tunica vaginalis of children with hydrocele in our study. It was thought that aquaporin-1 overexpression may play a role in non-communicating hydroceles in children. [Display omitted] [ABSTRACT FROM AUTHOR]

Objective: To explore the relationship between aquaporin-1 (AQP1) and endometrial adenocarcinoma.Method: Intratumoral microvessel density (IMD) was assessed as well as AQP1 and vascular endothelial growth factor expression in samples from 117 women, 75 with endometrioid adenocarcinoma, 17 with endometrial hyperplasia, and 25 with normal proliferative endometria.Results: AQP1 was located in the epithelial cells of microvessels and small vessels in all samples. The AQP1/IMD ratio was highest in samples from the first, less in samples from the second, and least in samples from the third group. In samples from endometrioid adenocarcinoma, the AQP1/IMD ratio was significantly correlated with histologic grade, surgical stage, myometrial invasion, and extrauterine metastasis. There was a positive correlation between AQP1 expression and IMD and between AQP1/IMD ratio and VEGF expression.Conclusion: AQP1 may be involved in the tumorigenesis and progression of endometrioid adenocarcinoma by promoting angiogenesis, and AQP1 level may be both a tumor indicator and a new therapeutic target. [ABSTRACT FROM AUTHOR]

Objective: Aquaporin-1 (AQP1), the osmotic water channel, is located in choroidal plexus, which facilitates the cerebrospinal fluid formation in central nervous system (CNS). AQP1 has been speculated to maintain the homeostasis of intracellular and extracellular water in the brain, while the intractable epilepsy (IE) may be related to the imbalance in water and ion homeostasis. Methods: To investigate the role of AQP1 in pathophysiology of IE, we studied the expression of AQP1 in surgical samples of the anterior temporal neocortex of patients with IE and the age-matched controls samples. Results: Using immunohistochemistry, it was shown that AQP1 expression increased in astrocytes, but not in neurons or oligodendrocytes. Double-label immunofluorescence and confocal microscopy disclosed AQP1 immunoreactivity at the astrocyte membranes, where the most abundant expression was in the perivascular glial processes, which were recognized with antiglial fibrillary acidic protein antibodies (anti-GFAP). Conclusion: For the first time, we showed high expression of AQP1 water channels in IE cases and suggest two mechanisms to explain this finding. Increased AQP1 expression of astrocytes may be a cause or a consequence of IE. Thus, additional works are needed to elucidate the true mechanism underlying their relationship. [ABSTRACT FROM AUTHOR]

Aquaporin (AQP)1 belongs to a ubiquitous family of water channel proteins characterized by sequence similarity and the presence of two NPA (Asp-Pro-Ala) motifs existing in almost all organs and tissues. Currently, 13 human AQPs are known and they are divided into two subgroups according to their ability to transport only water molecules, such as AQP1, or also glycerol and other small solutes. The genomic, structural and functional aspects of AQP1 are briefly described. An in-depth discussion is devoted to proteomic approaches that are useful for identifying and characterizing AQP1, mainly through electrophoretic techniques combined with different extraction procedures followed by mass spectrometry analysis. Moreover, the relevance of AQP1 in human diseases is also explained. Its role in human tumors and, in particular, those of the kidney (e.g., clear cell renal carcinoma) is discussed. [ABSTRACT FROM AUTHOR]

We have determined CO2 permeabilities, PCO2, of red cells of normal human blood and of blood deficient in various blood group proteins by a previously described mass spectrometric technique. While PCO2 of normal red cells is ~0.15 cm/s, we find in red blood cells (RBCs) lacking the Rh protein complex (Rhnull) a significantly reduced PCO2 of 0.07 cm/s ±0.02 cm/s (P<0.02). This value is similar to the value we have reported previously for RBCs lacking aquaporin-1 protein (AQP-1null), suggesting that each of the Rh and AQP-1 proteins is responsible for ~1/2 of the normal CO2 permeability of the RBC membrane. Four other blood group deficiencies tested lack diverse membrane proteins but exhibit normal CO2 permeability. The CO2 pathway constituted by Rh proteins was inhibitable at pHe= 7.4 by NH4CI with an I50 of ~10 mM corresponding to an I50 for NH3 of ~0.3 mM. The pathway independent of Rh proteins, presumably that constituted by AQP-1, was not inhibitable by NH4CI/NH3. However, both pathways were strongly inhibited by DIDS, which accounts for the marked inhibitory effect of DIDS on normal PCO2, while in contrast another AE1 inhibitor, DiBAC, does not inhibit PCO2, although it markedly reduces PHCO3-. We conclude that Rh protein, presumably the Rh-associated glycoprotein RhAG, possesses a gas channel that allows passage of CO2 in addition to NH3. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate whether the expression of AQP-1 on the pleura is altered in a rat model with a tuberculous pleural effusion (TPE) and to study its function. A TPE model was established by intrapleural inoculation with 0.03 mg (2 ml) standard tuberculosis bacillus (H37Rv). The rats with TPE were sacrificed at different time points (day 1, 3, or 5) after inoculation. The control group received a 2-ml intrapleural injection of saline. The visceral and parietal pleural tissues were harvested and processed for real-time RT-PCR, Western blot, immunohistochemistry, and determination of tissue AQP-1 levels. Recombinant adenovirus Ad-rAQP-1 containing full-length cDNA of AQP-1 was constructed. Six groups of seven Wistar rats were assigned to receive the following treatments: group 1: intrapleural administration of normal saline; group 2: intrapleural administration of tuberculosis bacilli (TB); group 3: intrapleural inoculation with TB at day 7 following intrapleural administration of Ad-rAQP-1 vector; group 4: intrapleural inoculation with 0.03 mg TB at day 7 following intrapleural administration of control Ad-GFP vector; group 5: intrapleural administration of Ad-rAQP-1; group 6: intrapleural administration of control Ad-GFP vector. The expression of AQP-l on the pleural tissue was detected by immunohistochemistry and Western blot analysis. Histopathologic changes of the pleura and the volume of pleural fluid were examined on day 7 following gene intervention or on day 3 following TB inoculation. Bilateral pleural effusions appeared within 5 days in all rats who received an intrapleural inoculation with TB. The peak amount of pleural fluid occurred on day 3. The AQP-1 expression at protein and mRNA was increased in the early phase of TPE. The expression of AQP-1 was increased in the Ad-rAQP-1 gene transfer group, indicating successful adenovirus gene transfer. The volume of pleural fluid in group 3 (6.1 ± 0.7 ml) was significantly increased compared with that in group 2 (3.8 ± 1.0 ml) and group 4 (4.0 ± 1.1 ml). These findings suggested that AQP-1 was increased in TPE and it may be involved in the formation of TPE. [ABSTRACT FROM AUTHOR]

Ultrafiltration (UF) failure is one of the most important causes of long-term peritoneal dialysis (PD) failure in patients. Osmotic forces acting across small and ultra-small pores generate a UF with solutes through the small pore and free water transport (FWT) through the ultra-small pore. The ability of glucose to exert an osmotic pressure sufficient to cause UF is the so-called ‘osmotic conductance to glucose’ (OCG) of the peritoneal membrane. Our study proposes a simple method to determine both the OCG and FWT. In 50 patients on PD, a Double Mini-Peritoneal Equilibration Test (Double Mini-PET), consisting of two Mini-PET, was performed consecutively. A solution of 1.36% glucose was used for the first test, whereas a solution of 3.86% glucose was used for the second test. The sodium removal values and the differences in UF between the two tests were used to calculate FWT and the OCG. Patients with UF failure showed significant reductions not only in the OCG and the FWT but also of UF of small pores. The Double Mini-PET is simple, fast, and could become useful to evaluate patients on PD in everyday clinical practice.Kidney International (2007) 72, 643–650; doi:10.1038/sj.ki.5002405; published online 4 July 2007 [ABSTRACT FROM AUTHOR]

Abstract: The treatment of most patients with head and neck cancer includes ionizing radiation (IR). Salivary glands in the IR field suffer significant and irreversible damage, leading to considerable morbidity. Previously, we reported that adenoviral (Ad)-mediated transfer of the human aquaporin-1 (hAQP1) cDNA to rat [C. Delporte, B.C. O''Connell, X. He, H.E. Lancaster, A.C. O''Connell, P. Agre, B.J. Baum, Increased fluid secretion after adenoviral-mediated transfer of the aquaporin-1 cDNA to irradiated rat salivary glands. Proc. Natl. Acad. Sci. U S A. 94 (1997) 3268-3273] and miniature pig [Z. Shan, J. Li, C. Zheng, X. Liu, Z. Fan, C. Zhang, C.M. Goldsmith, R.B. Wellner, B.J Baum, S. Wang. Increased fluid secretion after adenoviral-mediated transfer of the human aquaporin-1 cDNA to irradiated miniature pig parotid glands. Mol. Ther. 11 (2005) 444-451] salivary glands ∼16 weeks following IR resulted in a dose-dependent increase in salivary flow to ≥80% control levels on day 3. A control Ad vector was without any significant effect on salivary flow. Additionally, after administration of Ad vectors to salivary glands, no significant lasting effects were observed in multiple measured clinical chemistry and hematology values. Taken together, the findings show that localized delivery of AdhAQP1 to IR-damaged salivary glands is useful in transiently increasing salivary secretion in both small and large animal models, without significant general adverse events. Based on these results, we are developing a clinical trial to test if the hAQP1 cDNA transfer strategy will be clinically effective in restoring salivary flow in patients with IR-induced parotid hypofunction. [Copyright &y& Elsevier]

Abstract: Single-molecule atomic force microscopy (AFM) provides novel ways to characterize structure–function relationships of native membrane proteins. High-resolution AFM-topographs allow observing substructures of single membrane proteins at sub-nanometer resolution as well as their conformational changes, oligomeric state, molecular dynamics and assembly. Complementary to AFM imaging, single-molecule force spectroscopy experiments allow detecting molecular interactions established within and between membrane proteins. The sensitivity of this method makes it possible to detect the interactions that stabilize secondary structures such as transmembrane α-helices, polypeptide loops and segments within. Changes in temperature or protein–protein assembly do not change the position of stable structural segments, but influence their stability established by collective molecular interactions. Such changes alter the probability of proteins to choose a certain unfolding pathway. Recent examples have elucidated unfolding and refolding pathways of membrane proteins as well as their energy landscapes. We review current and future potential of these approaches to reveal insights into membrane protein structure, function, and unfolding as we recognize that they could help answering key questions in the molecular basis of certain neuro-pathological dysfunctions. [Copyright &y& Elsevier]

Abstract: Water channel proteins, known as aquaporins, are transmembrane proteins that mediate osmotic water permeability. In a previous study, we found that acetazolamide could inhibit osmotic water transportation across Xenopus oocytes by blocking the function of aquaporin-1 (AQP1). The purpose of the current study was to confirm the effect of acetazolamide on water osmotic permeability using the human embryonic kidney 293 (HEK293) cells transfected with pEGFP/AQP1 and to investigate the interaction between acetazolamide and AQP1. The fluorescence intensity of HEK293 cells transfected with pEGFP/AQP1, which corresponds to the cell volume when the cells swell in a hyposmotic solution, was recorded under confocal laser fluorescence microscopy. The osmotic water permeability was assessed by the change in the ratio of cell fluorescence to certain cell area. Acetazolamide, at concentrations of 1 and 10μM, inhibited the osmotic water permeability in HEK293 cells transfected with pEGFP/AQP1. The direct binding between acetazolamide and AQP1 was detected by surface plasmon resonance. AQP1 was prepared from rat red blood cells and immobilized on a CM5 chip. The binding assay showed that acetazolamide could directly interact with AQP1. This study demonstrated that acetazolamide inhibited osmotic water permeability through interaction with AQP1. [Copyright &y& Elsevier]

Abstract: Most neurons in the central nervous system and peripheral nervous system do not express water transporting protein, aquaporin (AQP). In the present study, we have demonstrated the presence of AQP1 immunoreactivity in a particular neuronal subtype in the enteric nervous system (ENS) of the rat ileum. AQP1-immunoreactive (IR) neurons simultaneously expressed a neuronal marker HuC/D. Moderate numbers of AQP1-IR neuronal somata were found in the myenteric plexus, and a very few were found in the submucosal plexus. AQP1-IR neurons can be classified as Dogiel type I cells, which have several short processes and a single long process. Many AQP1-IR fibers were found both in the myenteric and submucosal plexi. Many AQP1-IR varicose fibers were closely associated with neuronal somata in the ganglia, whereas other AQP1-IR fibers penetrated into the muscle layers. These results suggest that AQP1-IR neurons probably play a significant role within the ENS to control gut functions. [Copyright &y& Elsevier]

The peritoneal equilibration test (PET) with 3.86% glucose concentration (3.86%-PET) has been suggested to be more useful than the standard 2.27%-PET in peritoneal dialysis (PD), but no longitudinal data for 3.86%-PET are currently available. A total of 242 3.86%-PETs were performed in 95 incident PD patients, who underwent the first test during the first year of treatment and then once a year. The classical parameters of peritoneal transport, such as peritoneal ultrafiltration (UF), D/D0, and D/PCreat, were analyzed. In addition, the absolute dip of dialysate sodium concentration (ΔDNa), as an expression of sodium sieving, was studied. D/D0 was stable, and a progressive decrease in UF was observed after the second PET, whereas D/PCreat firstly increased and then stabilized. ΔDNa was the only parameter showing a progressive decrease over time. On univariate analysis, D/D0 and ΔDNa were found to be significantly associated with the risk of developing UF failure (risk ratio (RR) 0.987 (0.973–0.999), P=0.04, and RR 0.768 (0.624–0.933), P=0.007, respectively), but on multivariate analysis only ΔDNa showed an independent association with the risk of developing UF failure (RR 0.797 (0.649–0.965), P=0.020). UF, D/D0, and D/PCreat changed only in those patients developing UF failure, reflecting increased membrane permeability, whereas ΔDNa significantly decreased in all patients. The 3.86%-PET allows a more complete study of peritoneal membrane transport than the standard 2.27%-PET. ΔDNa shows a constant and significant reduction over time and is the only factor independently predicting the risk of developing UF failure in PD patients.Kidney International (2006) 69, 927–933. doi:10.1038/sj.ki.5000183; published online 18 January 2006 [ABSTRACT FROM AUTHOR]

Abstract: The red cell membrane has an exceptionally high permeability for CO2, P CO2 ≈0.15 cm/s, which is two to three orders of magnitude greater than that of some epithelial membranes and similarly greater than the permeability of the red cell membrane for HCO3 –. As shown previously, this high P CO2 can be drastically inhibited by 10 μM 4,4′-diisothiocyanato-2,2′-stilbenedisulfonate (DIDS), indicating that membrane proteins may be involved in this high gas permeability. Here, we have studied the possible contribution of several blood group proteins to CO2 permeation across the red cell membrane by comparing P CO2 of red cells deficient in specific blood group proteins with that of normal red cells. While P CO2 of normal red cells is ~0.15 cm/s and that of Fynull and Jknull red cells is similar, P CO2''s of Colton null (deficient in aquaporin-1) and Rhnull cells (deficient in Rh/RhAG) are both reduced to about 0.07 cm/s, i.e. to about one half. In addition, the inhibitory effect of DIDS is about half as great in Rhnull and in Colton null red cells as it is in normal red cells. We conclude that aquaporin-1 and Rh/RhAG proteins contribute substantially to the high permeability of the human red cell membrane for CO2. Together these proteins are responsible for 50% or more of the CO2 permeability of red cell membranes. The CO2 pathways of both proteins can be partly inhibited by DIDS, which is why this compound very effectively reduces membrane CO2 permeability. [Copyright &y& Elsevier]

Abstract: The expression of aquaporin-1 (AQP1) protein, a water channel, in the choroid plexus epithelium was examined in the rat to determine the role of AQP1 in the pathophysiology of systemic hyponatremia. Systemic hyponatremia was produced by coadministration of 30ml hypotonic dextrose solution (140mM) intraperitoneally and 3μg 1-deamino-8-d-arginine vasopressin (dDAVP) subcutaneously. This hydration protocol produced severe systemic hyponatremia: 2h after drug administration, normonatremic serum osmolarity and Na+ concentration (296±5mOsm/L and 140±5mM) were reduced to 252±5mOsm/L and 117±2mM, respectively. AQP1 expression in the third ventricle choroid plexus epithelium was determined by using immunohistochemistry and quantitative immunoblot analysis. After 2h of systemic hyponatremia, AQP1 expression was significantly increased by 28.2±2.7% (n =6, P <0.05), whereas it was attenuated to 15.7±2.2% (n =6, P <0.05) after 6h of systemic hyponatremia. In addition, TUNEL staining revealed apoptotic granule cells in the dentate gyrus (DG) adjacent to the third ventricle with a peak measured 2h after the start of the systemic hyponatremia protocol, while virtually no apoptotic granule cells left 6h after the start of the hyponatremic treatment. These findings suggest that AQP1-mediated excessive water influx into the brain through the blood-cerebrospinal fluid barrier during systemic hyponatremia may elevate the intracranial pressure and result in the apoptotic brain cell death. Thus, AQP1 in the choroid plexus may play an important role in the pathogenesis of systemic hyponatremia. [Copyright &y& Elsevier]

The changes in the expression of aquaporin-1 (AQP1) mRNA and protein in cultured human trabecular meshwork (HTM) cells treated with dexamethasone and transfected with antisense oligonucleotides (AS-ODN) were studied, and the implication of AQP1 regulation in corticosteroid-glaucoma and the possibility of AS-ODN inhibiting the AQP1 expression were evaluated. The cultured HTM cells in vitro were treated with different concentrations of dexamethasone and transfected with oligonucleotides for 5 days respectively. Then, total RNA and protein of HTM cells were extracted. The changes of AQP1 mRNA and protein were demonstrated qualitatively and quantitatively by RT-PCR and Western blot. Band intensities were detected by imaging analysis. There was a parallel relationship between the results of RT-PCR and those of Western blot. The expression levels of AQP1 mRNA and protein in dexamethasone-treated groups were increased initially and decreased later as dexamethasone concentration was stepped up. In the 0.04 μg/mL and 0.4 μg/mL groups, the levels of AQP1 were higher than in control group (0 μg/mL). In the 4 μg/mL and 40 μg/mL groups, the AQP1 expression levels were lower than in control group. AS-ODN could down regulate the expression of AQP1 mRNA and protein in a dose-dependent manner. At 5 μg/mL, down-regulation efficiency reached the maximum. There was no statistically significant difference in the expression of AQP1 mRNA and protein between all sense oligonucleotides groups and control group. It was suggested that dexamethasone may induce the changes of the AQP1 expression in HTM cells to be involved in the occurrence of corticosteroid-glaucoma. AS-ODN can down-regulate the AQP1 expression in HTM cells to some extent. [ABSTRACT FROM AUTHOR]

Yang JH, Shi YF, Chen XD, Qi WJ. The influence of aquaporin-1 and microvessel density on ovarian carcinogenesis and ascites formation. Int J Gynecol Cancer 2006; 16(Suppl. 1):400–405. This study aimed at investigating aquaporin-1 (AQP1) distribution and expression in primary ovarian epithelial tumors, correlating with clinicopathologic variables and intratumoral microvessel density (IMD). The AQP1 expression and IMD in 105 cases with primary epithelial ovarian tumors were measured by semiquantitative immunohistochemical technique. AQP1 was located mainly in microvessels and small vessels but seldom in tumor cells. Expression of AQP1 and IMD in ovarian malignant tumors was significantly higher than that in borderline tumors ( P= 0.000, P= 0.001, respectively), and that in borderline tumors was higher than in benign tumors ( P= 0.008, P= 0.028, respectively). The expression of AQP1 in FIGO stage III–IV was more than that in stage I–II ( P= 0.001), and cases with ascites volume greater than 1000 mL were more than cases with ascites volume less than 1000 mL ( P= 0.000). There is a positively correlated relationship between expression of AQP1 and IMD (correlation coefficient 0.60, P= 0.000) and between expression of AQP1 and ascites volume (correlation coefficient 0.57, P= 0.000). These data implicate that high AQP1 expression may play an important role in the ovarian carcinogenesis, progression, and ascites formation. Further studies into the mechanism of AQP1 regulation and the relationship between AQP1 expression and tumor angiogenesis may lead to novel therapies for ovarian carcinoma. [ABSTRACT FROM AUTHOR]

Functional and molecular characterization of a peritoneal dialysis model in the C57BL/6J mouse. Background. Animal models are important for understanding the physiology and pathophysiology of peritoneal transport during peritoneal dialysis (PD). Mechanistic investigations of rat and rabbit models of PD are mostly based on intervention studies using pharmacologic agents or blocking antibodies. These models may be limited by the time-course, lack of specificity, or side effects of such interventions. Genetically modified mice could provide an attractive alternative to the above models. In this study, we have characterized PD parameters and tested the effect of gender and dialysate volume and/or osmolality in the C57BL/6J mouse. Methods. Mice were submitted to a 2-hour peritoneal equilibration test in order to obtain permeability parameters. The expression of the water channel aquaporin-1 (AQP1) and endothelial NO synthase (eNOS) was investigated at the protein (immunoblotting, immunostaining) and mRNA[real-time reverse-transcription-polymerase chain reaction (RT-PCR)] levels. The potential effect of gender on these parameters was also studied. Results. Exposure of mice to 2 mL of 3.86% glucose dialysate yielded equilibration curves for urea and glucose, a sodium sieving, and a net ultrafiltration (UF) that were remarkably similar to those obtained in rats. The increase in dialysate volume (from 2 mL to 3 mL and 6 mL) resulted in a higher ultrafiltration and, for the highest volume, an increase in the diffusive mass transport coefficient (MTAC) for urea. The increase in dialysate glucose concentration (from 1.36% to 3.86% and 7%) resulted in increased sodium sieving and higher UF, whereas the MTAC for urea was unchanged. In comparison with males, females had a similar peritoneal transport rate for small solutes but a significantly lower sodium sieving, reflecting a lower AQP1 mRNA and protein expression in the peritoneum. Conclusion. These data demonstrate the structural and functional similarity between mouse and rat models of PD, and further emphasize the relevance of mouse models to understand PD in humans. They also suggest that gender may influence water transport and AQP1 expression in the peritoneum. [ABSTRACT FROM AUTHOR]

Abstract: The treatment of most head and neck cancer patients includes ionizing radiation (IR). Salivary glands in the IR field suffer irreversible damage. Previously, we reported that adenoviral (Ad)-mediated transfer of the human aquaporin-1 (hAQP1) cDNA to rat submandibular glands following IR restored salivary flow to near normal levels. It is unclear if this strategy is useful in larger animals. Herein, we evaluated AdhAQP1-mediated gene transfer after parotid gland IR (20 Gy) in the miniature pig. Sixteen weeks following IR, salivation from the targeted gland was decreased by >80%. AdhAQP1 administration resulted in a dose-dependent increase in parotid salivary flow to ∼80% of pre-IR levels on day 3. A control Ad vector was without significant effect. The effective AdhAQP1 dose was 2.5 × 105 pfu/μl infusate, a dose that leads to comparable transgene expression in murine and minipig salivary glands. Three days after Ad vector administration little change was observed in clinical chemistry and hematology values. These findings demonstrate that localized delivery of AdhAQP1 to IR-damaged salivary glands increases salivary secretion, without significant general adverse events, in a large animal model. [Copyright &y& Elsevier]

Aquaporin-1 (AQP1) water channel plays a critical role for water reabsorption in the urinary concentrating mechanism. AQP1 expression in renal cells is upregulated by hypertonicity, but not urea, suggesting the requirement of an osmotic gradient. To investigate whether AQP1 expression is regulated by apical and/or basolateral hypertonicity, murine renal medullary mIMCD-K2 cells grown on permeable support were exposed to hypertonic medium. When the medium on the apical or basolateral membrane side was switched to hypertonic, the transcellular osmotic gradient was dissipated within 8h. Basolateral hypertonicity increased AQP1 expression more than apical hypertonicity. Comparable apical and basolateral hypertonicity without a transcellular hypertonic gradient, however, increased AQP1 expression. Cell surface biotinylation experiments revealed that hypertonicity promoted AQP1 trafficking to both plasma cell membranes. These results indicate that AQP1 expression is predominantly mediated by basolateral hypertonicity but a transcellular osmotic gradient is not necessary for its induction. [Copyright &y& Elsevier]

Aquaporin water channels are a family of membrane proteins that facilitate water movement across biological membranes. Aquaporin-1 (AQP-1) has been found to be important in osmotic water movement across cell membranes of epithelial and endothelial barriers. However, the distribution of AQP-1 in many normal human tissues is still unknown. The aim of this study was to use immunohistochemistry and semiquantitative histomorphometric analysis to determine the tissue distribution and relative expression of AQP-1 in normal human tissues using tissue microarray (TMA) technology. The normal human TMAs employed in this study included cardiovascular, respiratory, gastrointestinal, hepatic and pancreatobiliary, oral, salivary, nasal, mammary, fetal, endocrine, genital tract, central and peripheral nervous systems, urinary tract, skin, cartilage, and other soft connective tissues. Immunohistochemistry and semiquantitative histomorphometric analysis confirmed the presence of AQP-1 in endothelial barriers of almost all tissues and in many epithelial barriers. AQP-1 was highly expressed in the renal cortex, choroid plexus, and pancreatic ducts. AQP-1 expression levels were surprisingly high in the anus, gallbladder, and liver; moderate expression was also detected in the hippocampus and ependymal cells of the central nervous system. This is the first report of AQP-1 protein distribution in normal human TMAs. These findings confirm the presence of AQP-1 in human endothelia and selected water-transporting epithelia and several new locations, including mammary epithelium, articular chondrocytes, synoviocytes, and synovial microvessels where AQP-1 may be involved in milk production, chondrocyte volume regulation, synovial fluid secretion, and homeostasis, respectively. [ABSTRACT FROM AUTHOR]

Aim: To determine whether glucose, NaCl and/or cholera toxin modify the expression of aquaporin-1 (AQP-1) water channel. Methods: Aquaporin-1 gene expression was studied using primary cultures of human renal proximal tubule epithelial (HRPTE) cells. Results:D-Glucose and NaCl (500 mosm/kg·H[sub 2] O each) enhanced AQP-1 expression 2.4-fold (p < 0.05) and 4.0-fold (p < 0.01), respectively, which could be blocked 73 and 70% (p < 0.01), respectively, by cholera enterotoxin (10[sup –7] M). Angiotensin II (10[sup –6] M and 10[sup –8] M), vasopressin (10[sup –8] M) and/or atrial natriuretic peptide (10[sup –8] M) did not affect AQP-1 expression. Hyperosmolar Reno-60 and Hypaque-76 contrast agents at 500 mosm/kg·H[sub 2] O and isomolar Visipaque at 25% (v/v) concentration(s) also increased AQP-1 expression 3.8- to 5.0-fold (p < 0.01) in HRPTE cells which also were inhibited by cholera toxin from 41% (p < 0.05) to 71% (p < 0.01). AQP-1 was translocated from the cytosol to the membrane of HRPTE cells and hyperosmolarity enhanced this translocation 2.5-fold (p < 0.01). Conclusions: The increased urinary concentrating ability in proximal segment of the diabetic kidney associated with increased plasma glucose may be mediated via glucose’s ability to enhance AQP-1 expression, which leads to a more concentrated urine. The decrease in urinary flow secondary to cholera toxin exposure, on the other hand, may be mediated indirectly by cholera toxin’s inhibition of aquaoporin-1 gene expression.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background. The intrarenal localization of metallothionein (MT) expression has not been studied in detail. Therefore, we investigated the effects of acute exposure to cadmium on the renal expression of MT. Methods. MT mRNA expression was estimated quantitatively at 2, 6, 24, and 72 h after the injection of cadmium (1 mg/kg) to the intraperitoneum of male Sprague-Dawley rats. The site of cadmium-induced MT mRNA expression was determined, by the reverse transcription polymerase chain reaction (RT-PCR), using microdissected tubules. Immunoblotting and immunohistochemistry were also performed, to determine the localization of MT protein. Results. The mRNAs of MT-I and MT-II were significantly upregulated at 2 h and peaked at 24 and 6 h, respectively. RT-PCR revealed the expression of cadmium-induced MT mRNA mainly in the proximal tubules. Immunoblotting detected a clear 14-kDa band corresponding to MT protein, and immunohistochemistry showed abundant MT protein in the renal cortices of cadmium-treated rats. Conclusions. Our findings suggest that the proximal tubules are responsible for the cadmium-induced renal expression of MT mRNA and protein. [ABSTRACT FROM AUTHOR]

Retinoids have been implicated in the control of cell proliferation, differentiation, and developmental processes. We report here that aquaporin-1 (AQP1) is specifically induced by retinoic acid (RA) in human erythroleukemia HEL cells. Both all-trans-RA (ATRA) and 9-cis-RA (9CRA) strongly induced the AQP1 mRNA and protein in a dose-dependent manner. AQP1 protein was mainly expressed in plasma membrane in cells induced by RAs. To identify the RA response element (RARE) in the human AQP1 promoter, the 5′-flanking region of AQP1 promoter was isolated and transient transfection experiment in HEL cells was performed. Deletion analysis of the AQP1 promoter revealed that one putative DR5-like RARE with five spaces was located in the region from −2218 to −2202; AGGGCAgggacAGGTGA. Electrophoretic mobility shift assay (EMSA) experiment demonstrated that two slowly migrated complexes (C1 and C2) capable of binding the RARE sequence were present in nuclear extracts prepared from cells and the complex C1 was strongly increased in nuclear extracts by RA stimulation. The complexes C1 and C2 were significantly abolished by an excess unlabeled probe. These results indicate that RAs strongly stimulate the human AQP1 gene expression through the RARE and define a novel role in the regulation of erythropoiesis. [Copyright &y& Elsevier]

The AQP1 gene is transcriptionally upregulated in response to hypertonicity. However, the molecular mechanism in hypertonicity-induced transcription in the AQP1 gene has been poorly understood. Here we report a novel hypertonicity response element (HRE) in the AQP1 gene. A critical cis-acting element to hypertonicity in the AQP1 promoter is located at −54 to −46 and the change from GCTCCCCCC to GCTTTCCCC completely abolished the hypertonic induction and osmotic response, thus implicating the importance of the first CC sequence in the region. Two prominent DNA–protein complexes were observed electrophoretic mobility shift assay (EMSA), and the band intensities in nuclear extracts from osmotically stressed cells were much higher than that of isotonic nuclear extracts. The EMSA supershift assay with anti-Sp1 antibody showed that two retarded bands did not bind to anti-Sp1 antibody, suggesting that the DNA binding proteins bound to the HRE are not Sp1 family proteins. These data suggest that the transcription of the AQP1 by hypertonicity in renal cells is upregulated by the interaction with putative DNA binding proteins to a novel HRE located at −54 to −46 in the AQP1 gene. [Copyright &y& Elsevier]

Background. Ultrafiltration (UF) failure often complicates peritoneal dialysis (PD). At least two molecules might be involved in UF failure: aquaporin‐1 (AQP1), a water channel thought to be the ultrasmall pore of the peritoneal membrane (PM), and nitric oxide (NO), which might regulate effective peritoneal surface area and microvascular permeability. [ABSTRACT FROM PUBLISHER]

Background: Cerebral malaria (CM) is associated with sequestration of parasitized red blood cells (PRBCs) in the capillaries. Often, the association of CM with cerebral oedema is related with high mortality rate. Morphological changes of the choroid plexus (CP) and caspase-3 expression in CM have not been reported. In addition, limited knowledge is known regarding the role of aquaporin (AQP)-1 in CM. The present study evaluated changes in the CP, explored apoptotic changes and AQP-1 expression in CP epithelial cells (CPECs) in fatal CM patients., Methods: CP from fatal Plasmodium falciparum malaria patients (5 non-CM [NCM], 16 CM) were retrieved and prepared for histopathological evaluation. Caspase-3 and AQP-1 expressions in CPECs were investigated by immunohistochemistry., Results: Histologically, apoptotic changes in CPECs were significantly observed in the CM group compared with the NCM and normal control (NC) groups (p < 0.05). These changes included cytoplasmic and nuclear condensation/shrinkage of CPECs and detachment of CPECs from the basement membrane. The apoptotic changes were positively correlated with caspase-3 expression in the nuclei of CPECs. In addition, AQP-1 expression in CPECs was significantly decreased in the CM group compared with the NCM and NC groups (all p < 0.001). A negative correlation (r s  =  - 0.450, p = 0.024) was documented between caspase-3 expression in the nuclei of CPECs and AQP-1., Conclusions: Apoptotic changes and altered AQP-1 expression may contribute to CPEC dysfunction and subsequently reduce cerebrospinal fluid production, affecting the water homeostasis in the brains of patients with CM., (© 2022. The Author(s).)

In this study, the neuroprotective effects of melatonin (MEL) with changes in apoptosis, inflammation, and histopathological morphology were evaluated in the medulla oblongata of cisplatin (CIS) administered rats. Although the side effects of CIS are known in many tissues, its reaction on the medulla oblongata and the molecular association underlying this effect is unclear. Male wistar albino rats were separated into four groups (control, CIS, CIS+MEL, and MEL) (n = 24). CIS and CIS+MEL groups were given 4 mg/kg CIS at 4-day intervals (days 1, 5, 9, and 13) by the first day of the study. The MEL and CIS+MEL groups were given 10 mg/kg MEL daily for 13 days. At the end of the study, the medulla oblongata sections of the rats were harvested on the 14th day, and the changes in gene expressions were examined. Expression levels of inflammation markers ( TNF-α and IL-6 ), apoptotic markers ( Bax and Casp-3 ), and Aqp-1 and Aqp-4 were found to significantly increase with CIS administration. On microscopic examination, hemorrhage, edema, and perivascular edema were detected in the CIS applied group compared with controls. MEL treatment significantly reduced perivascular edema (p = 0.0152) and hemorrhage (p = 0.0087). Besides, there was a significant difference between the control and CIS groups regarding pyknosis and a significant increase in pyknotic neurons in the CIS treatment group (p < 0.001). This study indicates that CIS treatment significantly impaired medulla oblongata, and combined treatment with MEL ameliorates the injury in rats., (© TÜBİTAK.)

The canonical function of aquaporin (AQP) water channels is to facilitate passive transport of water across cellular membranes making them essential in the regulation of body water homeostasis. Moreover, AQPs, including AQP1, have been found to be overexpressed in multiple cancer types, including breast cancer, where AQP1 overexpression is associated with poor prognosis. AQPs have been shown to affect cellular processes associated with cancer progression and spread including cell migration, angiogenesis, and proliferation. Moreover, AQPs can regulate levels of adhesion proteins at cell-cell junctions, a regulatory role, which is still largely unexplored in cancer. Understanding the molecular mechanisms of how AQP1 contributes to breast cancer progression and metastatic processes is essential to establish AQP1 as a biomarker and to develop targeted anticancer treatments for breast cancer patients. This mini-review focuses on the role of AQP1 in breast cancer., (© 2021 Scandinavian Societies for Medical Microbiology and Pathology.)

Objective: The study aimed to investigate the effects of quercetin on Aquaporin 1 (AQP1) translocation in high glucose condition and made an attempt to clarify the underlying mechanisms and provide new ideas for the treatment of diabetic cataract (DC)., Methods: The human lens epithelial line SRA01/04 cells were divided into groups mentioned below: normal glucose, high glucose with a specific time (0 h, 2 h, 4 h, 8 h, 12 h, 24 h), high glucose plus the phosphoinositide 3-kinase (PI3K) inhibitor LY294002, high glucose plus the mammalian target of rapamycin (mTOR) inhibitor rapamycin, and high glucose plus quercetin with different doses (2 μmol/L, 4 μmol/L and 8 μmol/L). The western blotting assay was used to detect the protein kinase B (Akt), phosphorylated protein kinase B (p-Akt), mammalian target of rapamycin (m- TOR), phosphorylated mammalian target of rapamycin (p-mTOR) and AQP1. Real-time polymerase chain reaction (RT-PCR) was used to detect the expression of AQP1. A Membrane and Cytosol Protein Extraction Kit was applied to separate membrane proteins. Immunofluorescence assay was performed to evaluate the expression and location of AQP1. The effect of quercetin on the expression of AQP1 and PI3K/Akt/mTOR signaling was detected., Results: AQP1 protein was found to be significantly increased in 24 hour when exposed to high glucose condition (P<0.01). LY294002 and rapamycin inhibited PI3K/Akt/mTOR and AQP1 expression (P<0.01), preventing the change of AQP1 location in the SRA01/04 plasma membrane (P<0.01). This effect was further proved by immunofluorescence. In different doses of quercetin groups (2 μmol/L, 4 μmol/L and 8 μmol/L), the phosphorylation of mTOR and Akt were decreased and AQP1 in the membrane was changed compared with high glucose group (P<0.01)., Conclusion: Quercetin significantly decreased the AQP1 elevation and prevented the change of AQP1 location through inhibiting the activation of the PI3K/Akt/mTOR signaling in high-glucose-- cultured SRA01/04 cells, which might have the preventable and inhibitory effects on the early development of diabetic cataract. The specific pathophysiological role of quercetin still needs to be verified., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The aquaporins are a rapidly expanding family of highly conserved proteins which function as transmembrane water channels. We have previously shown that the gene for aquaporin-1 (AQP-1) is expressed in rat, aortic vascular smooth muscle cells (VSMCs) implying a specific role for AQP-1 in vascular function. In this study we set out to document the expression of AQP-1 in human arteries and found mRNA and protein in normal endothelial and VSMCs of human arteries and capillaries and in a subset of VSMCs in human atherosclerotic plaques. Secondly, we examined the regulation of AQP-1 gene expression during vascular development and following vascular injury. Studies in the rat demonstrated that AQP-1 mRNA is induced in the neonatal aorta at week 2 of postnatal development and that the protein is present in neointimal VSMCs following balloon injury. Finally, by measuring the rate of change in cell size induced by changes in external osmolarity and demonstrating that water transport can be inhibited with mercuric chloride, we show that AQP-1 is responsible for water transport across human VSMC membranes. Thus, this study provides evidence for a hitherto unrecognised role for aquaporins in mediating rapid water transport across human VSMC membranes. By analogy with other tissues, these data argue for an important role for AQP-1 in regulating transcellular fluid flow and tissue hydration.Copyright © 1999 S.Karger AG, Basel [ABSTRACT FROM AUTHOR]

Despite the recent positional cloning of genes responsible for autosomal dominant polycystic kidney disease (ADPKD), the exact pathogenetic mechanisms underlying this disorder are still unclear. To learn more about cyst formation, we investigated cell differentiation and cell polarity in the Han:SPRD (cy/+) rat between 21 days and 60 wk of age. At early stages of cyst development, alkaline phosphatase, aquaporin-1, NaSi-1 cotransporter, and Na+-K+-adenosinetriphosphatase (Na+-K+-ATPase) were expressed normally. Clusterin mRNA was only sparsely expressed at the onset of cystic degeneration and increased thereafter, being highest in noncystic nephron segments. In cyst wall cells, clusterin on the one hand and alkaline phosphatase, aquaporin-1, NaSi-1-cotransporter, and Na+-K+-ATPase on the other were expressed in a mutually exclusive fashion. No change in cell polarity could be observed at any stage. Our data therefore argue against a change in cell polarity and against an early arrest in normal tubular development during cyst formation in the Han:SPRD (cy/+) rat model of ADPKD but favor the hypothesis that tubular epithelia develop in an orderly fashion and degenerate thereafter. [ABSTRACT FROM AUTHOR]