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1.
Nephrol Dial Transplant ; 25(7): 2077-89, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20494894

RESUMEN

Many patients with heart failure have underlying renal dysfunction, and similarly, patients with kidney failure are prone to cardiac failure. This has led to the concept of cardio-renal syndromes, which can be an acute or chronic cardio-renal syndrome, when cardiac failure causes deterioration in renal function, or acute and/or chronic Reno-Cardiac syndrome, when renal dysfunction leads to cardiac failure. Patients who develop these syndromes have increased risk of hospital admission and mortality. Although there are clinical guidelines for managing both heart failure and chronic kidney disease, there are no agreed guidelines for managing patients with cardio-renal and/or Reno-Cardiac syndromes, as these patients have typically been excluded from clinical trials. We have therefore reviewed the currently available published literature to outline a consensus of current best clinical practice for these patients.


Asunto(s)
Insuficiencia Cardíaca/terapia , Insuficiencia Renal/terapia , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/etiología , Humanos , Guías de Práctica Clínica como Asunto , Diálisis Renal , Insuficiencia Renal/complicaciones , Insuficiencia Renal/etiología , Síndrome
2.
São Paulo; Sciense Publishing Brasil; 2006. 270 p. il..
en Portugués | DANTEPAZZANESE, SESSP-IDPCACERVO | ID: dan-3697

Asunto(s)
Atlas , Nefrología
3.
Proc Natl Acad Sci U S A ; 98(23): 13414-9, 2001 Nov 06.
Artículo en Inglés | MEDLINE | ID: mdl-11687620

RESUMEN

The alpha and beta subunits of Na-K-ATPase are up-regulated by hypertonicity in inner-medullary collecting duct cells adapted to survive in hypertonic conditions. We examined the regulation of the gamma subunit by hypertonicity. Although cultured inner-medullary collecting duct cells lacked the gamma subunits, both variants gamma(a) and gamma(b) were expressed in cells adapted to 600 and 900 mosmol/KgH(2)O. This expression was reversible with a half-time of 17.2 +/- 0.5 h. The message of the gamma subunit was absent in isotonic conditions and increased with higher tonicity in adapted cells. In acute experiments the appearance of the gamma subunit was found to be both time-dependent (> or =24 h) and osmolality-dependent (> or =500 mosmol/KgH(2)O). No induction was noted with urea and only minimal induction with mannitol. Increasing concentrations of the phosphatidylinositol 3-kinase inhibitor LY294002 resulted in a dose-dependent decrement in the expression of the gamma subunit with total abolition at 10 microM. This was associated with a decrease in cell viability as <20% survived the treatment with 10 microM of LY294002. Neither inhibition of extracellular response kinase nor p38 mitogen-activated protein kinase inhibited osmotic induction of the gamma subunit. In contrast, cells transfected with a dominant negative c-Jun N-terminal kinase 2-APF construct displayed complete inhibition of the gamma subunit. Such cells have accelerated loss of viability in hypertonic conditions. This study describes the regulation of the gamma subunit of Na-K-ATPase by hypertonicity. This regulation is transcriptionally regulated and involves signaling mediated by phosphatidylinositol 3-kinase and c-Jun N-terminal kinase 2 pathways.


Asunto(s)
Proteínas Quinasas Activadas por Mitógenos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Animales , Secuencia de Bases , Northern Blotting , Western Blotting , Línea Celular , Cromonas/farmacología , Sondas de ADN , Inhibidores Enzimáticos/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Morfolinas/farmacología , Concentración Osmolar , Inhibidores de las Quinasa Fosfoinosítidos-3 , ATPasa Intercambiadora de Sodio-Potasio/química , ATPasa Intercambiadora de Sodio-Potasio/genética
4.
J Clin Invest ; 108(10): 1495-504, 2001 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-11714741

RESUMEN

In hepatocytes, Na+ influx through nonselective cation (NSC) channels represents a key point for regulation of cell volume. Under basal conditions, channels are closed, but both physiologic and pathologic stimuli lead to a large increase in Na+ and water influx. Since osmotic stimuli also activate mitogen-activated protein (MAP) kinase pathways, we have examined regulation of Na+ permeability and cell volume by MAP kinases in an HTC liver cell model. Under isotonic conditions, there was constitutive activity of p38 MAP kinase that was selectively inhibited by SB203580. Decreases in cell volume caused by hypertonic exposure had no effect on p38, but increases in cell volume caused by hypotonic exposure increased p38 activity tenfold. Na+ currents were small when cells were in isotonic media but could be increased by inhibiting constitutive p38 MAP kinase, thereby increasing cell volume. To evaluate the potential inhibitory role of p38 more directly, cells were dialyzed with recombinant p38alpha and its upstream activator, MEK-6, which substantially inhibited volume-sensitive currents. These findings indicate that constitutive p38 activity contributes to the low Na+ permeability necessary for maintenance of cell volume, and that recombinant p38 negatively modulates the set point for volume-sensitive channel opening. Thus, functional interactions between p38 MAP kinase and ion channels may represent an important target for modifying volume-sensitive liver functions.


Asunto(s)
Hígado/citología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Sodio/metabolismo , Animales , Permeabilidad de la Membrana Celular , Tamaño de la Célula , Inhibidores Enzimáticos/farmacología , Imidazoles/farmacología , Transporte Iónico , Hígado/enzimología , Hígado/metabolismo , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Concentración Osmolar , Piridinas/farmacología , Ratas , Células Tumorales Cultivadas , Proteínas Quinasas p38 Activadas por Mitógenos
5.
N Engl J Med ; 345(12): 851-60, 2001 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-11565517

RESUMEN

BACKGROUND: It is unknown whether either the angiotensin-II-receptor blocker irbesartan or the calcium-channel blocker amlodipine slows the progression of nephropathy in patients with type 2 diabetes independently of its capacity to lower the systemic blood pressure. METHODS: We randomly assigned 1715 hypertensive patients with nephropathy due to type 2 diabetes to treatment with irbesartan (300 mg daily), amlodipine (10 mg daily), or placebo. The target blood pressure was 135/85 mm Hg or less in all groups. We compared the groups with regard to the time to the primary composite end point of a doubling of the base-line serum creatinine concentration, the development of end-stage renal disease, or death from any cause. We also compared them with regard to the time to a secondary, cardiovascular composite end point. RESULTS: The mean duration of follow-up was 2.6 years. Treatment with irbesartan was associated with a risk of the primary composite end point that was 20 percent lower than that in the placebo group (P=0.02) and 23 percent lower than that in the amlodipine group (P=0.006). The risk of a doubling of the serum creatinine concentration was 33 percent lower in the irbesartan group than in the placebo group (P=0.003) and 37 percent lower in the irbesartan group than in the amlodipine group (P<0.001). Treatment with irbesartan was associated with a relative risk of end-stage renal disease that was 23 percent lower than that in both other groups (P=0.07 for both comparisons). These differences were not explained by differences in the blood pressures that were achieved. The serum creatinine concentration increased 24 percent more slowly in the irbesartan group than in the placebo group (P=0.008) and 21 percent more slowly than in the amlodipine group (P=0.02). There were no significant differences in the rates of death from any cause or in the cardiovascular composite end point. CONCLUSIONS: The angiotensin-II-receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes. This protection is independent of the reduction in blood pressure it causes.


Asunto(s)
Antagonistas de Receptores de Angiotensina , Antihipertensivos/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/tratamiento farmacológico , Tetrazoles/uso terapéutico , Adulto , Anciano , Amlodipino/efectos adversos , Amlodipino/uso terapéutico , Antihipertensivos/efectos adversos , Compuestos de Bifenilo/efectos adversos , Bloqueadores de los Canales de Calcio/uso terapéutico , Creatinina/sangre , Nefropatías Diabéticas/complicaciones , Método Doble Ciego , Femenino , Humanos , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Irbesartán , Fallo Renal Crónico/prevención & control , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Tetrazoles/efectos adversos
6.
Am J Physiol Renal Physiol ; 280(5): F768-76, 2001 May.
Artículo en Inglés | MEDLINE | ID: mdl-11292618

RESUMEN

Renal cells in culture have low viability when exposed to hypertonicity. We developed cell lines of inner medullary collecting duct cells adapted to live at 600 and 900 mosmol/kgH(2)O. We studied the three modules of the mitogen-activated protein (MAP) kinase family in the adapted cells. These cells had no increase in either extracellular signal-regulated kinase, c-Jun NH(2)-terminal kinase, or p38 MAP kinase protein or basal activity. When acutely challenged with further increments in tonicity, they had blunted activation of these kinases, which was not due to enhanced phosphatase activity. In contrast, the cells adapted to the hypertonicity displayed a marked increment in Na-K-ATPase expression (5-fold) and ouabain-sensitive Na-K-ATPase activity (10-fold). The changes were reversible on return to isotonic conditions. Replacement of 300 mosmol/kgH(2)O of NaCl by urea in cells adapted to 600 mosmol/kgH(2)O resulted in marked decrement in Na-K-ATPase and failure to maintain the cell line. Replacement of NaCl for urea in cells adapted to 900 mosmol/kgH(2)O did not alter either Na-K-ATPase expression, or the viability of the cells. The in vivo modulation of Na-K-ATPase was studied in the renal papilla of water-deprived mice (urinary osmolality 2,900 mosmol/kgH(2)O), compared with that of mice drinking dextrose in water (550 mosmol/kgH(2)O). Increased water intake was associated with a ~30% decrement in Na-K-ATPase expression (P < 0.02, n = 6), suggesting that this enzyme is osmoregulated in vivo. We conclude that whereas MAP kinases play a role in the response to acute changes in tonicity, they are not central to the chronic adaptive response. Rather, in this setting there is upregulation of other osmoprotective proteins, among which Na-K-ATPase appears to be an important component of the adaptive process.


Asunto(s)
Soluciones Hipertónicas , Proteínas Quinasas JNK Activadas por Mitógenos , Riñón/fisiología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Animales , Northern Blotting , Línea Celular , Supervivencia Celular , Células Cultivadas , Escherichia coli/metabolismo , Proteínas HSP70 de Choque Térmico/biosíntesis , Immunoblotting , Riñón/citología , Riñón/enzimología , Cinética , MAP Quinasa Quinasa 4 , Ratones , Quinasas de Proteína Quinasa Activadas por Mitógenos/farmacología , ARN/aislamiento & purificación , ATPasa Intercambiadora de Sodio-Potasio/biosíntesis , Equilibrio Hidroelectrolítico
7.
Oncology (Williston Park) ; 14(9 Suppl 8): 12-20, 2000 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-11033834

RESUMEN

Preclinical studies have shown that rhIL-11, also known as oprelvekin (Neumega), stimulates early and later stages of megakaryocytopoiesis (including proliferation and differentiation of megakaryocyte precursors and maturation of megakaryocytes), to produce an increase in peripheral platelet count. Because of these effects, rhIL-11 must be administered to patients with cancer sufficiently in advance of the platelet nadir (within 6 to 24 hours postchemotherapy) to allow adequate time for megakaryocyte maturation and platelet formation. Therefore, the maximum platelet response coincides with the time when the platelet nadir would normally be experienced. In myelosuppressed, nonhuman primates, optimal platelet response occurred following 14 days of treatment at a dose equivalent to the 50-microgram/kg daily dose recommended in humans; lower doses and shorter durations were less effective. These data support the current dosing recommendation in humans, which states that rhIL-11 dosing continues until platelet recovery to > or = 50,000/microL has been achieved for 2 consecutive days or for a total of 10 to 21 days in each cycle. The nonhematopoietic effects of rhIL-11 include a renal effect, resulting in plasma-volume expansion, as well as potential beneficial clinical effects in damaged or inflamed intestinal mucosa, including potential mitigation of mucositis and a rationale for future studies in inflammatory bowel disease.


Asunto(s)
Antineoplásicos/farmacología , Factores Estimulantes de Colonias/farmacología , Hematopoyesis/efectos de los fármacos , Interleucina-11/farmacología , Proteínas Recombinantes/farmacología , Animales , Plaquetas/efectos de los fármacos , Plaquetas/fisiología , Edema/inducido químicamente , Humanos , Interleucina-11/fisiología , Macaca fascicularis , Megacariocitos/efectos de los fármacos , Ratones , Modelos Animales , Membrana Mucosa/efectos de los fármacos , Equilibrio Hidroelectrolítico/efectos de los fármacos
9.
J Biol Chem ; 275(30): 23281-6, 2000 Jul 28.
Artículo en Inglés | MEDLINE | ID: mdl-10930430

RESUMEN

We have previously shown that hypertonicity stimulates cyclooxygenase-2 (COX-2) expression in cultured medullary epithelial cells. The aims of the present study were (i) to examine the role of cytoplasmic signaling through MAPK pathways in tonicity regulation of COX-2 expression in collecting duct cells and (ii) to assess the possible contribution of COX-2 to the survival of inner medullary collecting duct (IMCD) cells under hypertonic conditions. In mIMCD-K2 cells, a cell line derived from mouse IMCDs, hypertonicity induced a marked increase in COX-2 protein expression. The stimulation was reduced significantly by inhibition of MEK1 (PD-98059, 5-50 microm) and p38 (SB-203580, 5-100 microm) and was almost abolished by the combination of the two compounds. To study the role of JNK in tonicity-stimulated COX-2 expression, IMCD-3 cell lines stably transfected with dominant-negative mutants of three JNKs (JNK-1, -2, and -3) were used. Hypertonicity-stimulated COX-2 protein expression was significantly reduced in dominant-negative JNK-2-expressing cells and was unchanged in dominant-negative JNK-1- and JNK-3-expressing cells compared with controls. The reduction of COX-2 expression was associated with greatly reduced viability of dominant-negative JNK-2-expressing cells during hypertonicity treatment. 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) (2-8 microm), an inhibitor of Src kinases, reduced the tonicity-stimulated COX-2 expression in a dose-dependent manner, whereas PP3, an inactive analog of PP2, had no effect. Inhibition of COX-2 activity by NS-398 (30-90 microm) and SC-58236 (10-20 microm) significantly reduced viability of mIMCD-K2 cells subjected to prolonged hypertonic treatment. We conclude that 1) all three members of the MAPK family (ERK, JNK-2, and p38) as well as Src kinases are required for tonicity-stimulated COX-2 expression in mouse collecting duct cells and that 2) COX-2 may play a role in cell survival of medullary cells under hypertonic conditions.


Asunto(s)
Isoenzimas/metabolismo , Túbulos Renales Colectores/enzimología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Animales , Línea Celular , Ciclooxigenasa 2 , Dinoprostona/metabolismo , Activación Enzimática , Inhibidores Enzimáticos/farmacología , Isoenzimas/efectos de los fármacos , Proteínas Quinasas JNK Activadas por Mitógenos , Túbulos Renales Colectores/citología , Ratones , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas Activadas por Mitógenos/genética , Nitrobencenos/farmacología , Concentración Osmolar , Prostaglandina-Endoperóxido Sintasas/efectos de los fármacos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Sulfonamidas/farmacología
12.
Am J Kidney Dis ; 35(6): XLVII-L, 2000 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-10845848
13.
Am J Kidney Dis ; 34(5): 809-17, 1999 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-10561135

RESUMEN

Diabetic nephropathy is the most common cause of end-stage renal disease in the United States. We undertook a study to assess the impact of assignment to different levels of blood pressure control on the course of type 1 diabetic nephropathy in patients receiving angiotensin-converting enzyme (ACE) inhibitor therapy. We also examined the long-term course of this well-characterized cohort of patients receiving ACE inhibitor therapy. One hundred twenty-nine patients with type 1 diabetes and diabetic nephropathy who had previously participated in the Angiotensin-Converting Enzyme Inhibition in Diabetic Nephropathy Study who had a serum creatinine level less than 4.0 mg/dL were randomly assigned to a mean arterial blood pressure (MAP) goal of 92 mm Hg or less (group I) or 100 to 107 mm Hg (group II). Patients received varying doses of ramipril as the primary therapeutic antihypertensive agent. All patients were followed for a minimum of 2 years. Outcome measures included iothalamate clearance, 24-hour creatinine clearance, creatinine clearance estimated by the Cockcroft and Gault formula, and urinary protein excretion. The average difference in MAP between groups was 6 mm Hg over the 24-month follow-up. The median iothalamate clearance in group I was 62 mL/min/1.73 m(2) at baseline and 54 mL/min/1.73 m(2) at the end of the study compared with a baseline of 64 mL/min/1.73 m(2) and final 58 mL/min/1.73 m(2) in group II. There were no statistically significant differences in the rate of decline in renal function between groups. There was a significant difference in follow-up total urinary protein excretion between group I (535 mg/24 h) and group II (1,723 mg/24 h; P = 0.02). Thirty-two percent of 126 patients achieved a final total protein excretion less than 500 mg/24 h. Patients from groups I and II had equivalent rates of adverse events. In patients with type 1 diabetes mellitus and diabetic nephropathy, the MAP goal should be 92 mm Hg or less for optimal renoprotection, if defined as including decreased proteinuria. With the combination of ACE inhibition and intensive blood pressure control, many patients can achieve regression or apparent remission of clinical evidence of diabetic nephropathy.


Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Antihipertensivos/administración & dosificación , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Nefropatías Diabéticas/tratamiento farmacológico , Hipertensión Renal/tratamiento farmacológico , Ramipril/administración & dosificación , Adulto , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Antihipertensivos/efectos adversos , Presión Sanguínea/efectos de los fármacos , Diabetes Mellitus Tipo 1/diagnóstico , Nefropatías Diabéticas/diagnóstico , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Hipertensión Renal/diagnóstico , Recién Nacido , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Ramipril/efectos adversos , Resultado del Tratamiento
14.
J Clin Invest ; 102(10): 1874-81, 1998 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-9819374

RESUMEN

In cultured renal cells, hypertonicity activates multiple mitogen-activated protein kinases (MAPKs) and enhances the expression of heat shock proteins (HSPs). In rats, 24 h water restriction increased mean urinary osmolality (Uosm) from 2, 179+/-153 mOsm/kg to 2,944+/-294 mOsm/kg (P < 0.001) and was associated with significant (P < 0.05) increases in the papillary activity of c-Jun NH2-terminal protein kinase (JNK) by 22%, extracellular signal-regulated protein kinase (ERK) by 49%, and p38 MAPK by 15%. Conversely, 24 h of water-loading (Uosm 473+/-33 mOsm/kg) caused suppression of JNK activity by 43% (P < 0.001), ERK by 39% (P < 0.05), and p38 MAPK by 26% (P < 0.05). No such modulation was observed in the isotonic cortex. c-Jun phosphorylation was decreased in papilla from water-loaded rats by 45% versus controls. Expression of Hsp 110, inducible Hsp 70, and Hsp 25 was greater in the hyperosmotic papilla than the isosmotic cortex but was not affected by the animal's hydration state. In cultured inner medullary collecting duct cells, HSP expression was maximal at 500 mOsm/kg, while activation of JNK continued to increase. We conclude that under basal conditions of hydration, these HSPs are maximally expressed in the hypertonic inner medulla, while the activation of all three members of the MAPK family approaches but is not maximal.


Asunto(s)
Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Proteínas de Choque Térmico/metabolismo , Médula Renal/metabolismo , Proteínas Quinasas Activadas por Mitógenos , Equilibrio Hidroelectrolítico , Animales , Células Cultivadas , Immunoblotting , Masculino , Proteína Quinasa 9 Activada por Mitógenos , Fosforilación , Proteínas Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-jun/metabolismo , Ratas , Ratas Sprague-Dawley , Proteínas Quinasas p38 Activadas por Mitógenos
16.
Lancet ; 352(9123): 220-8, 1998 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-9683227

RESUMEN

Disorders of serum sodium are both the most common and probably most the poorly understood electrolyte disorders in clinical medicine. In the past few years increased knowledge about the non-osmotic release of vasopressin and the cloning of vasopressin receptors and of vasopressin-regulated water channels (AQP2) has enhanced our understanding of these disorders. Also controversies surrounding the treatment of hyponatraemic patients have led to well-accepted therapeutic guidelines.


Asunto(s)
Diabetes Insípida , Hipernatremia , Hiponatremia , Sodio , Humanos , Concentración Osmolar , Sodio/sangre , Sodio/fisiología
17.
Am J Kidney Dis ; 31(6): 1028-31, 1998 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-9631849

RESUMEN

A ovolactovegetarian patient presented with hyponatremia. She had maximally dilute urine and undetectable vasopressin levels. Dietary history revealed very low protein intake but no beer intake. We postulated that the very low intake of solute limited her water excretion and caused the hyponatremia despite only a modest increase in fluid intake. When protein intake was increased in a clinical research center setting, free water excretion increased and serum sodium normalized despite maintaining the water intake at 4 to 5 L daily. We discuss the role of dietary solute in water excretion. Previously described in beer drinkers, the phenomenon can occur in the absence of beer drinking. In this era of weight consciousness, hyponatremia because of low solute intake may be seen with increased frequency.


Asunto(s)
Ingestión de Líquidos/fisiología , Hiponatremia/etiología , Potasio en la Dieta/administración & dosificación , Sodio en la Dieta/administración & dosificación , Adulto , Cerveza/efectos adversos , Dieta Vegetariana/efectos adversos , Proteínas en la Dieta/administración & dosificación , Femenino , Humanos , Hiponatremia/orina , Concentración Osmolar , Orina
19.
J Biol Chem ; 273(2): 800-4, 1998 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-9422734

RESUMEN

The c-Jun NH2-terminal protein kinases (JNKs), as well as the extracellular signal-regulated protein kinases (ERKs) and p38 mitogen-activated protein kinase, are activated in renal cells in response to extracellular hypertonicity. To determine whether activation of JNKs by hypertonicity is isoform-specific, renal inner medullary collecting duct cells were stably transfected with cDNA's encoding hemagglutinin (HA)-tagged JNK1 and JNK2 isoforms, and the expressed kinases were immunoprecipitated with an anti-HA antibody. Whereas both recombinant kinases were equivalently expressed, only immunoprecipitates from the HA-JNK2 cells displayed hypertonicity-inducible JNK activity. Furthermore, expression of dominant-negative JNK2 (HA-JNK2-APF) in stable clones inhibited hypertonicity-induced JNK activation by 40-70%, whereas expression of dominant-negative JNK1 (HA-JNK1-APF) had no significant inhibitory effect. Independent HA-JNK2-APF (but not HA-JNK1-APF) clones displayed greatly reduced viability relative to neomycin controls after 16 h of exposure to 600 mosM/kg hypertonic medium with percent survival of 20.5 +/- 2.7 and 31.5 +/- 7.3 for two independent HA-JNK2-APF clones compared with 80.1 +/- 1.0 for neomycin controls (p < 0.001, n = 5, mean +/- S.E.). However, neither JNK mutant blocked either regulatory volume increase or hypertonicity-induced enhancement of uptake of inositol, an organic osmolyte putatively involved in long term adaptation to hypertonicity. These results define JNK2 as the primary hypertonicity-activated JNK isoform in IMCD-3 cells and demonstrate its central importance in cellular survival in a hypertonic environment by a mechanism independent of acute regulatory volume increase as well as regulation of organic osmolyte uptake.


Asunto(s)
Médula Renal/metabolismo , Túbulos Renales Colectores/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos , Proteínas Quinasas/metabolismo , Adaptación Fisiológica , Transporte Biológico , Línea Celular Transformada , Activación Enzimática , Médula Renal/citología , Médula Renal/fisiología , Túbulos Renales Colectores/citología , Túbulos Renales Colectores/fisiología , MAP Quinasa Quinasa 7 , Concentración Osmolar
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