RESUMO
OBJECTIVES: The study objective was to assess the association between angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) use and mortality in patients with chronic kidney disease (CKD). BACKGROUND: There is insufficient evidence about the association of ACEI or ARBs with mortality in patients with CKD. METHODS: A logistic regression analysis was used to calculate the propensity of ACEI/ARB initiation in 141,413 U.S. veterans with nondialysis CKD who were previously unexposed to ACEI/ARB treatment. We examined the association of ACEI/ARB administration with all-cause mortality in patients matched by propensity scores using the Kaplan-Meier method and Cox models in "intention-to-treat" analyses and in generalized linear models with binary outcomes and inverse probability of treatment weights in "as-treated" analyses. RESULTS: The age of the patients at baseline was 75 ± 10 years, 8% of patients were black, and 22% were diabetic. ACEI/ARB administration was associated with a significantly lower risk of mortality both in the intention-to-treat analysis (hazard ratio: 0.81, 95% confidence interval: 0.78 to 0.84; p < 0.001) and the as-treated analysis with inverse probability of treatment weights (odds ratio: 0.37, 95% confidence interval: 0.34 to 0.41; p < 0.001). The association of ACEI/ARB treatment with lower risk of mortality was present in all examined subgroups. CONCLUSIONS: In this large contemporary cohort of nondialysis-dependent patients with CKD, ACEI/ARB administration was associated with greater survival.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/mortalidade , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Angiotensina/metabolismo , Insuficiência Renal Crônica/metabolismoRESUMO
BACKGROUND: Collectrin is an orphan member of the renin-angiotensin system and is a homolog of angiotensin-converting enzyme 2, sharing ≈50% sequence identity. Unlike angiotensin-converting enzyme 2, collectrin lacks any catalytic domain. Collectrin has been shown to function as a chaperone of amino acid transporters. In rodents, the renal expression of collectrin is increased after subtotal nephrectomy and during high-salt feeding, raising the question of whether collectrin has any direct role in blood pressure regulation. METHODS AND RESULTS: Using a susceptible genetic background, we demonstrate that deletion of collectrin results in hypertension, exaggerated salt sensitivity, and impaired pressure natriuresis. Collectrin knockout mice display impaired endothelium-dependent vasorelaxation that is associated with vascular remodeling, endothelial nitric oxide synthase uncoupling, decreased nitric oxide production, and increased superoxide generation. Treatment with Tempol, a superoxide scavenger, attenuates the augmented sodium sensitivity in collectrin knockout mice. We report for the first time that collectrin is expressed in endothelial cells. Furthermore, collectrin directly regulates l-arginine uptake and plasma membrane levels of CAT1 and y(+)LAT1 amino acid transporters in endothelial cells. Treatment with l-arginine modestly lowers blood pressure of collectrin knockout mice. CONCLUSIONS: Collectrin is a consequential link between the transport of l-arginine and endothelial nitric oxide synthase uncoupling in hypertension.
Assuntos
Hipertensão Renal/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Peptidil Dipeptidase A/genética , Enzima de Conversão de Angiotensina 2 , Animais , Arginina/metabolismo , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Feminino , Hipertensão Renal/genética , Hipertensão Renal/fisiopatologia , Rim/metabolismo , Rim/fisiopatologia , Pulmão/citologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Knockout , Natriurese/fisiologia , Óxido Nítrico/metabolismo , Peptidil Dipeptidase A/metabolismo , Cultura Primária de Células , Cloreto de Sódio na Dieta/farmacologia , Superóxidos/metabolismoRESUMO
OBJECTIVES: This study sought to compare the association of microalbuminuria with outcomes in patients with different comorbidities. BACKGROUND: The risk of adverse outcomes associated with lower levels proteinuria has been found to be linearly decreasing with even low-normal levels of microalbuminuria. It is unclear whether comorbid conditions change these associations. METHODS: We examined the association of urine microalbumin-creatinine ratio (UACR) with mortality and the slopes of estimated glomerular filtration rate (eGFR) in a nationally representative cohort of 298,875 U.S. veterans. Associations of UACR with all-cause mortality overall and in subgroups of patients with and without diabetes mellitus, hypertension, cardiovascular disease, congestive heart failure, and advanced chronic kidney disease (CKD) were examined in Cox models, and with the slopes of eGFR in linear and logistic regression models. RESULTS: Very low levels of UACR were linearly associated with decreased mortality and less progression of CKD overall: adjusted mortality hazard ratio and estimated glomerular filtration rate slope (95% confidence interval [CI]) associated with UACR ≥200 µg/mg, compared to <5 µg/mg were 1.53 (95% CI: 1.38 to 1.69, p < 0.001) and -1.59 (95% CI: -1.83 to -1.35, p < 0.001). Similar linearity was present in all examined subgroups, except in patients with CKD in whom a U-shaped association was present and in whom a UACR of 10 to 19 was associated with the best outcomes. CONCLUSIONS: The association of UACR with mortality and with progressive CKD is modified in patients with CKD, who experience higher mortality and worse progression of CKD with the lowest levels of UACR. Proteinuria-lowering interventions in patients with advanced CKD should be implemented cautiously, considering the potential for adverse outcomes.
Assuntos
Albuminúria , Doenças Cardiovasculares , Causas de Morte , Diabetes Mellitus , Insuficiência Renal Crônica , Idoso , Albuminúria/complicações , Albuminúria/diagnóstico , Albuminúria/epidemiologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/urina , Comorbidade , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/urina , Progressão da Doença , Modificador do Efeito Epidemiológico , Feminino , Taxa de Filtração Glomerular , Humanos , Incidência , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Modelos de Riscos Proporcionais , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/urina , Fatores de Risco , Estados UnidosRESUMO
BACKGROUND AND OBJECTIVES: Depression is common and is associated with higher mortality in patients with ESRD or CKD (stage 5). Less information is available on earlier stages of CKD. This study aimed to determine the prevalence of depression and any association with all-cause mortality in patients with varying severity of nondialysis-dependent CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a retrospective study of a national cohort of 598,153 US veterans with nondialysis-dependent CKD stages 1-5 followed for a median of 4.7 years in the US Department of Veterans Affairs Health System. Diagnosis of depression was established as a result of systematic screening and administration of antidepressants. Association of depression with all-cause mortality overall and stratified by CKD stages were examined with the Kaplan-Meier method and in Cox models. RESULTS: There were 179,441 patients (30%) with a diagnosis of depression. Over median follow-up of 4.7 years, depression was associated with significantly higher age-adjusted mortality overall (hazard ratio, 1.55; 95% confidence interval, 1.54-1.57; P<0.001). Sequential adjustments for sociodemographic characteristics and especially for comorbid conditions attenuated this association, which nevertheless remained significant (hazard ratio, 1.25; 95% confidence interval, 1.23-1.26). CONCLUSIONS: In this large cohort of predominantly elderly male patients with CKD, prevalence of depression and antidepressant use is high (30%) and is associated with significantly higher all-cause mortality independent of comorbid conditions.
Assuntos
Antidepressivos/uso terapêutico , Depressão/epidemiologia , Insuficiência Renal Crônica/mortalidade , Insuficiência Renal Crônica/psicologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Depressão/tratamento farmacológico , Depressão/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos RetrospectivosRESUMO
BACKGROUND: Hyponatremia is common in patients with conditions such as congestive heart failure and is associated with increased mortality in hospitalized patients. Congestive heart failure is common in patients with chronic kidney disease, but the association of serum sodium concentration with mortality in such patients is not well characterized. METHODS AND RESULTS: We examined the association of serum sodium concentration with all-cause mortality in a nationally representative cohort of 655 493 US veterans with non-dialysis-dependent chronic kidney disease (95 961 [15%] of them with congestive heart failure). Associations were examined in time-dependent Cox models with adjustment for potential confounders. During a median follow-up of 5.5 years, a total of 193 956 patients died (mortality rate, 62.5/1000 patient-years; 95% confidence interval, 62.2-62.8). The association of serum sodium level with mortality was U-shaped, with the lowest mortality seen in patients with sodium level of 140 mEq/L and with both lower and higher levels showing significant associations with increased mortality. Patients with serum sodium levels of <130, 130 to 135.9, 145.1 to 150, and ≥150 mEq/L compared with 136 to 145 mEq/L had multivariable-adjusted mortality hazard ratios (95% confidence interval) of 1.93 (1.83-2.03), 1.28 (1.26-1.30), 1.33 (1.28-1.38), and 1.56 (1.33-1.83) (P<0.001 for all). The associations remained consistent in subgroups of patients with and without congestive heart failure. CONCLUSIONS: Both lower and higher serum sodium levels are independently associated with higher mortality in patients with non-dialysis-dependent chronic kidney disease, irrespective of the presence or absence of congestive heart failure.
Assuntos
Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/mortalidade , Hipernatremia/complicações , Hiponatremia/complicações , Nefropatias/epidemiologia , Nefropatias/mortalidade , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Doença Crônica , Comorbidade , Feminino , Seguimentos , Insuficiência Cardíaca/sangue , Humanos , Hipernatremia/sangue , Hiponatremia/sangue , Incidência , Nefropatias/sangue , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Índice de Gravidade de Doença , Sódio/sangue , Taxa de SobrevidaRESUMO
BACKGROUND: The interrelationship of left ventricular hypertrophy (LVH) with ejection fraction (EF) and their impact on mortality in non-dialysis-dependent chronic kidney disease (NDD-CKD) is unclear. METHODS: We examined the associations of EF and LVH with all-cause mortality in a historic cohort of 650 male US veterans with moderate-to-advanced NDD-CKD. EF and LVH were examined both separately and after categorizing patients according to their concomitant EF and presence/absence of LVH. Associations with mortality were examined in Cox models with adjustments for demographics, blood pressure, comorbidities, smoking status, medication use and biochemical characteristics. RESULTS: EF <30 and 30-50% were associated with higher all-cause mortality compared to EF >50% even after multivariable adjustments [multivariable adjusted hazard ratio, 95% confidence interval (CI): 2.83 (1.86-4.30) and 1.38 (1.06-1.78), P < 0.001 for linear trend]. LVH in itself was not associated with mortality [multivariable adjusted hazard ratio, 95% CI: 0.83 (0.66-1.05), P = 0.12], but the presence of LVH combined with an EF <50% was associated with the highest mortality [multivariable adjusted hazard ratios, 95% CI in patients with EF >50% + LVH, EF ≤ 50%-LVH and EF ≤ 50% + LVH, compared to EF >50%-LVH: 0.84 (0.63-1.13), 1.36 (1.00-1.83) and 1.62 (1.07-2.46)]. CONCLUSIONS: Low EF is associated with higher mortality in patients with NDD-CKD. In the presence of a low EF, LVH is also associated with higher mortality. Clinical trials are needed to determine if interventions targeting patients with low EF and LVH can lower mortality in NDD-CKD.
Assuntos
Causas de Morte , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/mortalidade , Insuficiência Renal Crônica/mortalidade , Volume Sistólico , Distribuição por Idade , Idoso , Estudos de Coortes , Comorbidade , Ecocardiografia Doppler/métodos , Humanos , Hipertrofia Ventricular Esquerda/terapia , Incidência , Estimativa de Kaplan-Meier , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/mortalidade , Falência Renal Crônica/terapia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Modelos de Riscos Proporcionais , Diálise Renal , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/terapia , Estudos Retrospectivos , Índice de Gravidade de Doença , Análise de SobrevidaRESUMO
BACKGROUND: The efficacy of 25-hydroxyvitamin D (25[OH]D) supplementation versus vitamin D receptor activators for the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) stages 3 or 4 and vitamin D deficiency is unclear. STUDY DESIGN: Randomized controlled trial. SETTING & PARTICIPANTS: 80 patients with CKD stages 3 or 4, 25(OH)D level <30 ng/mL, and SHPT in a single medical center. INTERVENTION: Ergocalciferol, 50,000 units, titrated to achieve serum levels ≥30 ng/mL versus paricalcitol, 1 or 2 µg/d, for 16 weeks. OUTCOMES: The occurrence of 2 consecutive parathyroid hormone (PTH) levels decreased by at least 30% from baseline. All analyses were intention to treat. RESULTS: Baseline characteristics in the 2 groups were similar. 21 patients (53%) on paricalcitol and 7 patients (18%) on ergocalciferol treatment achieved the primary outcome measure (P = 0.002). After 16 weeks, PTH levels did not decrease significantly in patients receiving ergocalciferol, but were decreased significantly in those treated with paricalcitol (mean estimate of between-group difference over 16 weeks of therapy, 43.9 pg/mL; 95% CI, 11.2-76.6; P = 0.009). Serum 25(OH)D levels increased significantly after 16 weeks in only the ergocalciferol group, but not the paricalcitol group (mean estimate of between-group difference over 16 weeks of therapy, 7.08 ng/mL; 95% CI, 4.32-9.85; P < 0.001). Episodes of hyperphosphatemia and hypercalcemia were not significantly different between the 2 groups. LIMITATIONS: Lack of blinding and use of surrogate end points. CONCLUSIONS: Paricalcitol is more effective than ergocalciferol at decreasing PTH levels in patients with CKD stages 3 or 4 with vitamin D deficiency and SHPT.
Assuntos
Ergocalciferóis/uso terapêutico , Hiperparatireoidismo Secundário/tratamento farmacológico , Hiperparatireoidismo Secundário/etiologia , Insuficiência Renal Crônica/complicações , Vitaminas/uso terapêutico , Idoso , Feminino , Humanos , Masculino , Índice de Gravidade de DoençaRESUMO
Diabetic nephropathy is a complex and poorly understood disease process, and our current treatment options are limited. It remains critical, then, to identify novel therapeutic targets. Recently, a developmental protein and one of the bone morphogenetic protein antagonists, Gremlin, has emerged as a novel modulator of diabetic nephropathy. The high expression and strong co-localization with transforming growth factor-beta1 in diabetic kidneys suggests a role for Gremlin in the pathogenesis of diabetic nephropathy. We have constructed a gremlin siRNA plasmid and have examined the effect of Gremlin inhibition on the progression of diabetic nephropathy in a mouse model. CD-1 mice underwent uninephrectomy and STZ treatment prior to receiving weekly injections of the plasmid. Inhibition of Gremlin alleviated proteinuria and renal collagen IV accumulation 12 weeks after the STZ injection and inhibited renal cell proliferation and apoptosis. In vitro experiments, using mouse mesangial cells, revealed that the transfect ion of gremlin siRNA plasmid reversed high glucose induced abnormalities, such as increased cell proliferation and apoptosis and increased collagen IV production. The decreased matrix metalloprotease level was partially normalized by transfection with gremlin siRNA plasmid. Additionally, we observed recovery of bone morphogenetic protein-7 signaling activity, evidenced by increases in phosphorylated Smad 5 protein levels. We conclude that inhibition of Gremlin exerts beneficial effects on the diabetic kidney mainly through maintenance of BMP-7 activity and that Gremlin may serve as a novel therapeutic target in the management of diabetic nephropathy.
Assuntos
Proteína Morfogenética Óssea 7/metabolismo , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/terapia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Plasmídeos/genética , RNA Interferente Pequeno/fisiologia , Animais , Apoptose/genética , Apoptose/fisiologia , Western Blotting , Proteína Morfogenética Óssea 7/genética , Proliferação de Células , Células Cultivadas , Citocinas , Nefropatias Diabéticas/genética , Ensaio de Imunoadsorção Enzimática , Imuno-Histoquímica , Imunoprecipitação , Marcação In Situ das Extremidades Cortadas , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Camundongos , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína Smad5/genética , Proteína Smad5/metabolismoRESUMO
Glutathione S-transferase-micro1, GSTM1, belongs to a superfamily of glutathione S-transferases that metabolizes a broad range of reactive oxygen species and xenobiotics. Across species, genetic variants that result in decreased expression of the Gstm1 gene are associated with increased susceptibility for vascular diseases, including atherosclerosis in humans. We previously identified Gstm1 as a positional candidate in our gene mapping study for susceptibility to renal vascular injury characterized by medial hypertrophy and hyperplasia of the renal vessels. To determine the role of Gstm1 in vascular smooth muscle cells (VSMCs), we isolated VSMCs from mouse aortas. We demonstrate that VSMCs from the susceptible C57BL/6 mice have reduced expression of Gstm1 mRNA and its protein product compared with that of the resistant 129 mice. After serum stimulation, C57BL/6 VSMCs proliferate and migrate at a much faster rate than 129 VSMCs. Furthermore, C57BL/6 VSMCs have higher levels of reactive oxygen species and exhibit exaggerated p38 mitogen-activated protein kinase phosphorylation after exposure to H(2)O(2). To establish causality, we show that knockdown of Gstm1 by small interfering RNA results in increased proliferation of VSMCs in a dose-dependent manner, as well as in increased reactive oxygen species levels and VSMC migration. Moreover, Gstm1 small interfering RNA causes increased p38 mitogen-activated protein kinase phosphorylation and attenuates the antiproliferative effect of Tempol. Our data suggest that Gstm1 is a novel regulator of VSMC proliferation and migration through its role in handling reactive oxygen species. Genetic variants that cause a decremental change in expression of Gstm1 may permit an environment of exaggerated oxidative stress, leading to susceptibility to vascular remodeling and atherosclerosis.
Assuntos
Aterosclerose/metabolismo , Aterosclerose/patologia , Glutationa Transferase/metabolismo , Músculo Liso Vascular/citologia , Músculo Liso Vascular/enzimologia , Animais , Antioxidantes/farmacologia , Aorta/citologia , Divisão Celular/fisiologia , Movimento Celular/fisiologia , Células Cultivadas , Óxidos N-Cíclicos/farmacologia , Glutationa Transferase/genética , Peróxido de Hidrogênio/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Oxidantes/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Fosforilação/fisiologia , RNA Interferente Pequeno , Espécies Reativas de Oxigênio/metabolismo , Especificidade da Espécie , Marcadores de Spin , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Collectrin is a downstream target of the transcription factor hepatocyte nuclear factor-1alpha (HNF-1alpha), which is mutated in maturity-onset diabetes of the young subtype 3 (MODY3). Evidence from transgenic mouse models with collectrin overexpression in pancreatic islets suggests divergent roles for collectrin in influencing beta-cell mass and insulin exocytosis. To clarify the function of collectrin in the pancreas, we used a mouse line with targeted deletion of the gene. We examined pancreas morphology, glucose homeostasis by ip glucose tolerance testing (IPGTT) and insulin tolerance testing (IPITT), and pancreas function by in vivo acute-phase insulin response determination and glucose-stimulated insulin secretion from isolated islets. We find no difference in either pancreas morphology or function between wild-type and collectrin-deficient animals (Tmem27(-/y)). However, we note that by 6 months of age, Tmem27(-/y) mice exhibit increased insulin sensitivity by IPITT and decreased adiposity by dual-energy x-ray absorptiometry scanning compared with wild-type. We have previously reported that Tmem27(-/y) mice exhibit profound aminoaciduria due to failed renal recovery. We now demonstrate that Tmem27(-/y) animals also display inappropriate excretion of some short-chain acylcarnitines derived from amino acid and fatty acid oxidation. We provide further evidence for compensatory up-regulation of oxidative metabolism in Tmem27(-/y) mice, along with enhanced protein turnover associated with preserved lean mass even out to 1.5 yr of age. Our studies suggest that collectrin-deficient mice activate a number of adaptive mechanisms to defend energy homeostasis in the setting of ongoing nutrient losses.
Assuntos
Fator 1-alfa Nuclear de Hepatócito/metabolismo , Insulina/metabolismo , Glicoproteínas de Membrana/deficiência , Reação de Fase Aguda/metabolismo , Adiposidade/efeitos dos fármacos , Aminoácidos/sangue , Animais , Peso Corporal/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Jejum/sangue , Alimentos , Glucose/farmacologia , Teste de Tolerância a Glucose , Resistência à Insulina , Secreção de Insulina , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Glicoproteínas de Membrana/metabolismo , Camundongos , Fenótipo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Magreza/sangue , Magreza/metabolismo , Fatores de TempoRESUMO
BACKGROUND: Collectrin, a homologue of angiotensin converting enzyme 2, is expressed in pancreatic beta cells and renal proximal tubular and collecting duct cells under the control of hepatocyte nuclear factors-1alpha and -1beta. Because collectrin interacts with the soluble N-ethylmaleiamide-sensitive factor attachment protein receptor (SNARE) complexes, we investigated whether collectrin is involved in sodium handling in hypertension by vesicle trafficking of apical membrane proteins. METHODS AND RESULTS: Collectrin physically interacts with the SNARE complex: snapin, synaptosomal-associated protein 23 kDa, syntaxin-4, and vesicle-associated membrane protein-2 in mIMCD-3 cells. siRNA knockdown of collectrin resulted in a reduction in membrane-associated aquaporin-2, alpha-epithelial Na+ channel, and H+-ATPase. Collectrin and SNARE proteins were abundantly expressed in collecting ducts of Wistar-Kyoto rats. Wistar-Kyoto rats and spontaneously hypertensive rats 7 weeks of age were subjected to normal-salt (1% NaCl) and high-salt (8% NaCl) chow for 10 weeks. High-salt chow prominently elevated blood pressure, oral intake, and urinary excretion of NaCl and water in both groups. Although urinary excretion of aldosterone was significantly suppressed in both groups, collectrin expression was upregulated and associated with the maintenance of aquaporin-2, alpha-epithelial Na+ channel, and H+-ATPase in membrane fractions. Collectrin promoter activities and mRNA and protein expressions were upregulated and ubiquitinated collectrin was reduced by high NaCl (175 to 225 mmol/L) and not altered by 1 micromol/L aldosterone in mIMCD-3 cells. CONCLUSIONS: Upregulation of collectrin by high NaCl independent of aldosterone functionally links to the trafficking of apical membrane proteins via the SNARE complex, and collectrin may be responsible for the sodium retention in salt-sensitive hypertension.
Assuntos
Colectinas/biossíntese , Hipertensão/induzido quimicamente , Complexos Multiproteicos/metabolismo , Proteínas SNARE/metabolismo , Cloreto de Sódio/toxicidade , Regulação para Cima/efeitos dos fármacos , Aldosterona/urina , Animais , Aquaporina 2/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Linhagem Celular , Canais Epiteliais de Sódio , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Fator 1-beta Nuclear de Hepatócito/metabolismo , Hipertensão/metabolismo , Células Secretoras de Insulina/metabolismo , Túbulos Renais Coletores/metabolismo , Túbulos Renais Proximais/metabolismo , ATPases Translocadoras de Prótons/metabolismo , Proteínas Qa-SNARE/metabolismo , RNA Interferente Pequeno/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Proteína 2 Associada à Membrana da Vesícula/metabolismoRESUMO
Defects in renal proximal tubule transport manifest in a number of human diseases. Although variable in clinical presentation, disorders such as Hartnup disease, Dent's disease, and Fanconi syndrome are characterized by wasting of solutes commonly recovered by the proximal tubule. One common feature of these disorders is aminoaciduria. There are distinct classes of amino acid transporters located in the apical and basal membranes of the proximal tubules that reabsorb >95% of filtered amino acids, yet few details are known about their regulation. We present our physiological characterization of a mouse line with targeted deletion of the gene collectrin that is highly expressed in the kidney. Collectrin-deficient mice display a reduced urinary concentrating capacity due to enhanced solute clearance resulting from profound aminoaciduria. The aminoaciduria is generalized, characterized by loss of nearly every amino acid, and results in marked crystalluria. Furthermore, in the kidney, collectrin-deficient mice have decreased plasma membrane populations of amino acid transporter subtypes B(0)AT1, rBAT, and b(0,+)AT, as well as altered cellular distribution of EAAC1. Our data suggest that collectrin is a novel mediator of renal amino acid transport and may provide further insight into the pathogenesis of a number of human disease correlates.