Influencia de las acuaporinas en la génesis de múltiples enfermedades / Aquaporins Influence in the Genesis of Multiple Diseases

Las acuaporinas son una familia de proteínas que forman los canales de agua de la membrana. Están involucradas en una gran variedad de funciones fisiológicas y enfermedades humanas como el glaucoma, cáncer, epilepsia, obesidad entre otras. El descubrimiento de las acuaporinas cambia el panorama con respecto a la comprensión del transporte de agua en las membranas biológicas y a la naturaleza de las proteínas transportadoras en general, porque su estudio demuestra que existen canales en las membranas no sólo permeables a iones y que los movimientos de agua a través de las membranas son regulados por la célula en forma muy diferente a como se pensaba hace una década, esto implica comprender mejor los mecanismos fisiopatológicos que lleven al desarrollo de nuevas medidas terapéuticas y más eficaces para el tratamiento de las enfermedades.

Aquaporins are a family of membrane water channels. They are involved in a great variety of physiological functions and human diseases including, glaucoma, cancer, epilepsy, obesity among others. The discovery of the aquaporins have changed the view regarding the understanding of the transportation of water in the biological membranes and to the nature of the transporting proteins in general, because its study has showed that there are canals not only in permeable membranes to ions and the fact that the movements of water through the membranes are regulated by the cell in very different way, comparing to the considerations that existed a decade ago, this allows the understanding of physiopathologic mechanisms that lead to the development of therapeutic new measures better and more effective for the diseases treatment.

Neuromielitis óptica con alta expresión de acuaporina-4 y anticuerpos anti-acuaporina-4 positivos en suero / Neuromyelitis optica with high aquaporin-4 expression and positive serum aquaporin-4 autoantibodies

La presencia de anticuerpos IgG en suero, con blanco en los canales de acuaporina-4, es específica de la neuromielitis óptica (NMO). El 60% de los pacientes con NMO presentan lesiones cerebrales en la resonancia magnética (RM); en un 8% (mayoría niños) estas lesiones se consideraron "atípicas". Presentamos dos pacientes con NMO y lesiones en el SNC de alta expresión de acuaporina-4. Caso 1: varón de 50 años, que comenzó con pérdida de visión en ojo derecho (OD). Recibió tratamiento empírico con metilprednisolona 1 g/d x 3 días. Al mes presentó dolor generalizado y hemiparesia derecha; nuevamente recibió metilprednisolona 1 g/d x 5 días e IgG IV 400 mg/kg/d × 5 días. Recuperó la deambulación persistiendo el dolor y fenómenos paroxísticos en los 4 miembros. Potenciales evocados visuales: P100, ojo izquierdo (OI) 123 mseg. OD sin respuesta. La RM de cerebro (FLAIR) mostró hiperintensidad en nervio óptico derecho, hipotálamo y comisura blanca anterior. RM cervical: lesión medular extensa (5 cuerpos vertebrales). Caso 2: mujer de 53 años, con disminución de la agudeza visual en ambos ojos y parestesias en miembros inferiores que remitieron espontáneamente. Evolucionó al mes con cuadriparesia e incontinencia esfinteriana. Recibió metilprednisolona 1 g/d x 5 días, sin mejoría. Potenciales evocados visuales: P100 OI 124 mseg. OD 128 mseg. RM cerebro: (FLAIR) hiperintensidad hipotalámica y periacueductal. RM cervical: lesión medular extensa (7 cuerpos vertebrales). Anticuerpos anti-acuaporina-4 positivos en ambos pacientes (inmunofluorescencia indirecta). Las lesiones consideradas "atípicas", como aquí, en sitios con alta densidad de proteínas canales de agua AQP4 deberán considerarse para el diagnóstico diferencial.

Disease-specific aquaporin-4 antibodies (NMO-IgG) are the main effector of lesions in neuromyelitis optica (NMO) patients. Brain MRI lesions are detected in 60% of them, with 8% (almost infants) at sites of high aquaporin-4 expression. Patient 1: A fifty-year-old male with loss of vision in the right eye. Empiric treatment with metilprednisolone 1g/d for 3 days was indicated. After 30 days he complained of generalized pain, and a right hemiparesis was evident. The patient received bolus of metilprednisolone 1g/d for 5 days plus IgG 400 mg/kg/d IV for 5 days. He recovered ambulation but persisted with pain and paroxysmal phenomena (Lhermitte). Visual Evoked Potentials (VEP): P100 left eye 123 ms, right eye without response. Brain MRI (FLAIR) showed hyperintensity in the right optic nerve, hypothalamus and anterior white commissure. Cervical MRI showed extensive spinal cord lesion to an extension of 5 vertebral bodies. Patient 2: A fifty-three-year-old female who referred decreased visual acuity in both eyes and paresthesia in lower limbs which subsided spontaneously. One month later the patient evolved with cuadriparesis and sphincter incontinence. No improvement was observed with bolus of metilprednisolone 1g/d for 5 day. VEP: P100 left eye 124 ms, right eye 128 ms. Brain MRI (FLAIR) disclosed hypothalamic and periaqueductal hyperintensity. Cervical MRI showed extensive spinal cord lesion to an extension of 7 vertebral bodies. NMO-IgG antibodies were positive in both patients (indirect immunofluorescence assay). NMO brain lesions at sites of high aquaporin-4 expression, once considered "atypical" for their topography and infrequency in adults, should be borne in mind when considering differential diagnosis.

Enhanced Expression of Aquaporin-9 in Rat Brain Edema Induced by Bacterial Lipopolysaccharides / 华中科技大学学报（医学）（英德文版）

To investigate the role of AQP9 in brain edema,the expression of AQP9 in an infectious rat brain edema model induced by the injection of lipopolysaccharide (LPS) was examined.Immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) analysis demonstrated that the expressions of AQP9 mRNA and protein at all observed intervals were significantly increased in LPS-treated animals in comparison with the control animals.Time-course analysis showed that the first signs of blood-brain barrier disruption and the increase of brain water content in LPS-treated animals were evident 6 h after LPS injection,with maximum value appearing at 12 h,which coincided with the expression profiles of AQP9 mRNA and protein in LPS-treated animals.The further correlation analysis revealed strong positive correlations among the brain water content,the disruption of the blood-brain barrier and the enhanced expressions of AQP9 mRNA and protein in LPS-treated animals.These results suggested that the regulation of AQP9 expression may play important roles in water movement and in brain metabolic homeostasis associated with the pathophysiology of brain edema induced by LPS injection.

Autonomic Neural Regulation of Sodium Transporters and Water Channels in Rat Submandibular Gland

The present study was undertaken to explore the role of autonomic nerves in the regulation of sodium transporters and water channels in the salivary gland. Rats were denervated of their sympathetic or parasympathetic nerves to the submandibular gland. One week later, the expression of Na,K-ATPase, epithelial sodium channels (ENaC), and aquaporins (AQP) was examined in the denervated and contralateral glands. The sympathetic denervation slightly but significantly decreased the expression of alpha1 subunit of Na,K-ATPase, whereas the parasympathetic denervation increased it. The expression of alpha-subunit of ENaC was significantly increased in both the denervated and contralateral glands either by the sympathetic or parasympathetic denervation. The sympathetic denervation significantly increased the expression of AQP5 in both the denervated and contralateral glands, whereas the parasympathetic denervation decreased it. It is suggested that the autonomic nerves have a tonic effect on the regulation of sodium transporters and AQP water channels in the salivary gland.

Sympathetic and parasympathetic regulation of sodium transporters and water channels in rat submandibular gland

The present study was aimed to explore the role of sympathetic and parasympathetic nerves in the regulation of sodium transporters and water channels in the salivary gland. Rats were denervated of their sympathetic and parasympathetic nerves to the submandibular gland, and the glandular expression of sodium transporters and water channels was determined by Western blot analysis. The expression of either alpha1 or beta1 subunit of Na, K-ATPase was not significantly affected either by the sympathetic or by the parasympathetic denervation. The expression of subunits of epithelial sodium channels was significantly increased both in the denervated and contralateral glands either by the sympathetic or by the parasympathetic denervation. Neither the sympathetic nor the parasympathetic denervation significantly altered the expression of aquaporin-1 (AQP1). Nor was the expression of AQP4 affected significantly by the parasympathetic or the sympathetic denervation. On the contrary, the expression of AQP5 was significantly increased not only by the parasympathetic but also by the sympathetic denervation. These results suggest that sympathetic and parasympathetic nerves have tonic regulatory effects on the regulation of certain sodium transporters and AQP water channels in the salivary gland.

Blunted Indomethacin-Induced Downregulation of Aquaporins by Nitric Oxide Synthesis Inhibition in Rats

The present study was aimed to determine whether nitric oxide (NO) plays a role in the regulation of aquaporin (AQP) channels in the kidney. Male Brattleboro rats (250~300 g body weight) were used. The experimental group was treated with N(G)-nitro-L-arginine methyl ester (L-NAME, 100 mg/L drinking water) for 1 week, and cotreated with indomethacin (5 mg/kg, twice a day, i.p.) for the last two days. Control groups were treated with either L-NAME for 1 week, indomethacin for 2 days, or without any drug treatment. The abundance of AQP1, AQP2 and AQP3 proteins in the kidney was determined by Western blot analysis. Indomethacin downregulated AQP channels, whereas L-NAME by itself showed no significant effects on them. The indomethacin-induced downregulation of AQP2 and AQP3 was significantly blunted in L-NAME-treated rats, while that of AQP1 was not affected. These results suggest that endogenous NO, when stimulated, may downregulate AQP channels that are specifically regulated by AVP/cAMP pathway in the kidney.

Altered expression of sodium transporters and water channels following sympathetic and parasympathetic denervation in rat submandibular gland

The flow of saliva is controlled entirely by nervous stimuli. The present study was aimed to explore the role of sympathetic and parasympathetic nerves in the regulation of sodium transporters and water channels in the salivary gland. Rats were denervated of their sympathetic and parasympathetic nerves to the submandibular gland, and the expression of sodium transporters and water channels was determined. The expression of either alpha-1 or beta-1 subunit of Na, K-ATPase was not significantly affected by the sympathetic denervation. On the contrary, the expression of both subunits was decreased by the parasympathetic denervation. The expression of alpha-, beta-, and gamma-subunits of ENaC was not significantly affected by the sympathetic denervation, but was increased by the parasympathetic denervation. On the contrary, the expression of NHE3 was markedly decreased by both the sympathetic and the parasympathetic denervation. The sympathetic denervation significantly increased the expression of AQP1, while the parasympathetic denervation was without effect. The sympathetic and parasympathetic denervation significantly increased the expression of AQP4. The sympathetic denervation did not affect the expression of AQP5, but the parasympathetic denervation significantly decreased it. These results suggest that sympathetic and parasympathetic nerves have tonic effects on the regulation of sodium transporters and AQP water channels in the salivary gland. The sympathetic and parasympathetic denervation may then result in alterations of secretory rate and electrolyte composition of the saliva.

Effects of Bilateral Ureteral Obstruction on Renal Aquaporin Expression / 대한신장학회잡지

BACKGROUND: Obstruction of urinary tract is common cause of renal disfunction. Recent discovery of aquaporin water channels expressed in the kidney and various organs has faciliated our understanding of water transport across the permeable epithelial cell membrane. This study was performed to investigate the effects of bilateral ureteral obstruction on renal expression and cellular distribution of these water channels in rat kidney. METHODS: Male Sprague-Dawley rats were divided two groups. The abdominal cavity was opened and 2-0 silk ligatures were proximally placed on both ureters in experimental group. Sham-operated group was treated in the same procedures except ligation. After closure of the abdomen, the animals were maintained for 48 hr while being given food and water ad libitum. Kidney sections of both groups were processed for immunohistochemistry using antibodies to aquaporin-1, 2, 3, and 4. RESULTS: Immunoreactivity for aquaporin-1 of sham-operated kidney was detected in the apical and basolateral plasma membrane of proximal tubules and thin limb of Henle loop. That of bilateral ureteral obstructed kidney was decreased in the both tubules, especially in the proximal tubules and thin limb of Henle loop of inner medulla. Immunoreactivity for aquaporin-2 of sham-operated kidney was the most prominent in apical region and moderate in cytoplasm of the principal cells of entire collecting ducts. That of obstructed kidney was markedly decreased in entire collecting duct, especially inner medulla except inner stripe of outer medulla. The decrease was in parallel between the apical region and cytoplasm. Immunoreactivity for aquaporin-3 of sham-operated kidney was the most prominent in the basolateral plasma membrane of principal cells of entire collecting duct. That of obstructed kidney was decreased in entire collecting duct. Papillary epithelium was stained in obstructed kidney. Immunoreactivity for aquaporin-4 of sham-operated kidney was moderate in the basolateral plasma membrane of principal cells of collecting ducts of inner stripe of outer medulla and inner medulla. In obstructed kidney, immunoreactivity was detected in cortical and outer stripe of outer medullary collecting duct, and decreased in inner stripe of outer medulla and inner medulla. A marked heterogeneity was observed in inner medullary collecting duct. CONCLUSION: These results indicate that alterations of expression of aquaporin proteins after bilateral ureteral obstruction may lead to change in renal functions, such as urine concentrating ability.

Role of Nitric Oxide in the Regulation of Aquaporin-2 Water Channels in Rat Kidney / 대한신장학회잡지

BACKGROUND: The present study was aimed at investigating whether there is a mechanism exerted by endogenous nitric oxide(NO) in the regulation of aquaporin(AQP) water channels in the kidney. METHODS: Male Sprague-Dawley rats were treated with N(G)-nitro-L-arginine methyl ester(L-NAME, 40 mg/L drinking water) to inhibit the endogenous generation of nitric oxide. Four weeks later, total abundance and shuttling of AQP2 proteins were determined in different regions of the kidney. RESULTS: Chronic inhibition of NO synthesis increased the expression of AQP2 channels in cortex, outer medulla, and inner medulla of the kidney. The AQP2 shuttling was not significantly altered, as evidenced by an unaltered ratio of AQP2 expression in the membrane fraction versus that in the cytoplasmic fraction. CONCLUSION: It is suggested that endogenous NO activity plays a tonic inhibitory role in the expression of AQP2 channels in the kidney.

Decreased Expression of Aquaporin-2 Water Channels in the Kidney in Rats Treated with Chlorpropamide / 대한신장학회잡지

BACKGROUND: Whether blood glucose levels may change the regulation of aquaporin(AQP) water channels in the kidney was investigated. METHODS: Male Sprague-Dawley rats were treated with chlorpropamide(40 mg/100 g body weight per day, per oral, for 7 days), and their expression of AQP1-3 and type VI adenylyl cyclase proteins was determined in the kidney. RESULTS: Following the treatment with chlorpropamide, the blood glucose level was significantly decreased compared with that in the control(64+/-8 vs 106+/-7 mg/dL, n=6 each, p < 0.01). Accordingly, the expression of AQP2 proteins was decreased in the cortex, outer medulla, and inner medulla. The AQP2 targeting was not significantly altered, as evidenced by parallel decreases of its expression in the membrane and the cytoplasmic fractions. No significant changes were observed in the expression of either AQP1 or of AQP3. The protein expression of type VI adenylyl cyclase was not significantly altered. CONCLUSION: These results suggest that hypoglycemia attenuates the expression of AQP2 water channels in the kidney.

Aquaporin water channels in exocrine glands

No abstract available.