RESUMEN
Severe vitamin D deficiency (reduction in serum 25(OH)D concentration) in infants and children can cause features of the Fanconi syndrome, including phosphaturia, glycosuria, aminoaciduria, and renal tubular acidosis. This indicates that vitamin D and its metabolites influence proximal tubule function. Filtered 25(OH)D bound to vitamin D binding protein (DBP) is endocytosed by megalin-cubilin in the apical membrane. Intracellular 25(OH)D is metabolized to 1,25(OH)2D or calcitroic acid by 1-α-hydroxylase or 24-hydroxylase in tubule cell mitochondria. Bone-produced fibroblast growth factor 23 (FGF23) bound to Klotho in tubule cells and intracellular phosphate concentrations are regulators of 1-α-hydroxylase activity and cause proximal tubule phosphaturia. Aminoaciduria occurs when amino acid transporter synthesis is deficient, and 1,25(OH)2D along with retinoic acid up-regulate transporter synthesis by a vitamin D response element in the promoter region of the transporter gene. This review discusses evidence gained from studies in animals or cell lines, as well as from human disorders, that provide insight into vitamin D-proximal tubule interactions.
Asunto(s)
Túbulos Renales Proximales/metabolismo , Aminoacidurias Renales/etiología , Deficiencia de Vitamina D/complicaciones , Vitamina D/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/genética , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/metabolismo , Animales , Factor-23 de Crecimiento de Fibroblastos , Predisposición Genética a la Enfermedad , Humanos , Túbulos Renales Proximales/fisiopatología , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Pronóstico , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Aminoacidurias Renales/genética , Aminoacidurias Renales/metabolismo , Aminoacidurias Renales/fisiopatología , Factores de Riesgo , Transducción de Señal , Deficiencia de Vitamina D/genética , Deficiencia de Vitamina D/metabolismo , Deficiencia de Vitamina D/fisiopatología , Vitamina D3 24-Hidroxilasa/genética , Vitamina D3 24-Hidroxilasa/metabolismoRESUMEN
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.
Asunto(s)
Túbulos Renales Proximales/fisiopatología , Glicoproteínas de Membrana/deficiencia , Aminoacidurias Renales/fisiopatología , Sistemas de Transporte de Aminoácidos/genética , Animales , Femenino , Masculino , Glicoproteínas de Membrana/fisiología , Ratones , Concentración OsmolarRESUMEN
Heteromeric amino acid transporters (HATs) are composed of a heavy (SLC3 family) and a light (SLC7 family) subunit. Mutations in system b(0,+) (rBAT-b(0,+)AT) and in system y(+)L (4F2hc-y(+)LAT1) cause the primary inherited aminoacidurias (PIAs) cystinuria and lysinuric protein intolerance, respectively. Recent developments [including the identification of the first Hartnup disorder gene (B0AT1; SLC6A19)] and knockout mouse models have begun to reveal the basis of renal and intestinal reabsorption of amino acids in mammals.
Asunto(s)
Sistemas de Transporte de Aminoácidos/genética , Proteínas Portadoras/química , Proteínas Portadoras/genética , Cistinuria/genética , Aminoacidurias Renales/genética , Animales , Cistinuria/fisiopatología , Humanos , Aminoacidurias Renales/fisiopatologíaRESUMEN
Shortened red cell life span and excess iron cause functional and physiological abnormalities in various organ systems in thalassemia patients. In an earlier study, we showed that beta-thalassemia patients have a high prevalence of renal tubular abnormalities. The severity correlated with the degree of anemia, being least severe in patients on hypertransfusion and iron chelation therapy, suggesting that the damage might be caused by the anemia and increased oxidation induced by excess iron deposits. This study was designed to define the renal abnormalities associated with alpha-thalassemia and to correlate the renal findings with clinical parameters. Thirty-four pediatric patients (mean age 8.2+/-2.8 years) with Hb H disease or Hb H/Hb CS were studied. Ten patients (group 1) were splenectomized, with a mean duration post splenectomy of 3.5+/-1.4 years; 24 patients (group 2) had intact spleens. The results were compared with 15 normal children. Significantly higher levels of urine N-acetyl-beta- d-glycosaminidase, malondialdehyde (MDA), and beta(2)-microglobulin were found in both groups compared with normal children. An elevated urine protein/creatinine ratio was recorded in 60% of group 1 and 29% of group 2. Two patients (5.9%), 1 in each group, had generalized aminoaciduria. We found proximal tubular abnormalities in alpha-thalassemia patients. Increased oxidative stress, possibly iron induced, may play an important role, since urine MDA levels were significantly increased in both groups of patients.
Asunto(s)
Enfermedades Renales/etiología , Enfermedades Renales/fisiopatología , Túbulos Renales/fisiopatología , Talasemia alfa/complicaciones , Talasemia alfa/fisiopatología , Acetilglucosaminidasa/orina , Adolescente , Nitrógeno de la Urea Sanguínea , Niño , Preescolar , Creatinina/sangre , Humanos , Malondialdehído/orina , Estrés Oxidativo , Aminoacidurias Renales/etiología , Aminoacidurias Renales/fisiopatología , Bazo , Esplenectomía , Microglobulina beta-2/orinaRESUMEN
Plasma and urine levels of free amino acids were measured in 15 severely traumatized adult patients while they were receiving fluids free of calories and nitrogen. Endogenous plasma clearance and the relative rates of reabsorption of free amino acids from renal tubules were calculated. These data were compared with similar studies of eight control subjects. Multiple injury provoked distinct patterns of free amino acids in plasma and urine. Hypoaminoacidemia and hyperaminoaciduria were seen in severe trauma. There was a marked depletion of nonessential amino acids in plasma of trauma victims. In contrast, the urinary loss of all amino acids was increased 5-10 times. This enhanced loss in patients, however, represented only 2.1% of total N excreted compared with 0.7% in control subjects. Considerable variations were seen in the selectivity with which various amino acids were reabsorbed by renal tubules. This may partly be due to the abnormal pattern of amino acids presented to renal tubules.
Asunto(s)
Aminoácidos/orina , Traumatismo Múltiple/orina , Absorción , Adolescente , Adulto , Anciano , Femenino , Humanos , Túbulos Renales/fisiopatología , Masculino , Persona de Mediana Edad , Traumatismo Múltiple/sangre , Traumatismo Múltiple/complicaciones , Nitrógeno/orina , Aminoacidurias Renales/sangre , Aminoacidurias Renales/etiología , Aminoacidurias Renales/fisiopatología , Aminoacidurias Renales/orinaAsunto(s)
Síndrome de Fanconi/fisiopatología , Riñón/fisiopatología , Aminoácidos/metabolismo , Animales , Transporte Biológico , Glucosuria/metabolismo , Humanos , Iminoácidos/metabolismo , Riñón/efectos de los fármacos , Túbulos Renales/metabolismo , Maleatos/metabolismo , Metales/toxicidad , Fosfatos/metabolismo , Aminoacidurias Renales/fisiopatologíaAsunto(s)
Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica , Osteomalacia , Raquitismo , Acidosis Tubular Renal/fisiopatología , Anticonvulsivantes/efectos adversos , Enfermedades de las Vías Biliares/complicaciones , Neoplasias Óseas/complicaciones , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/etiología , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/fisiopatología , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/terapia , Cistinosis/fisiopatología , Síndrome de Fanconi/fisiopatología , Displasia Fibrosa Ósea/complicaciones , Humanos , Hipofosfatasia/fisiopatología , Enfermedades Renales/complicaciones , Túbulos Renales/fisiopatología , Síndromes de Malabsorción/complicaciones , Neoplasias/complicaciones , Neurofibromatosis 1/complicaciones , Osteomalacia/inducido químicamente , Osteomalacia/etiología , Osteomalacia/fisiopatología , Osteomalacia/terapia , Síndromes Posgastrectomía , Aminoacidurias Renales/fisiopatología , Raquitismo/inducido químicamente , Raquitismo/etiología , Raquitismo/fisiopatología , Raquitismo/terapiaAsunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Enfermedades Renales/fisiopatología , Túbulos Renales/fisiopatología , Defectos Congénitos del Transporte Tubular Renal/fisiopatología , Equilibrio Ácido-Base , Acidosis Tubular Renal/fisiopatología , Aminoácidos/metabolismo , Angiotensina II/biosíntesis , Transporte Biológico , Niño , Preescolar , Cistinuria/fisiopatología , Glicina/metabolismo , Enfermedad de Hartnup/fisiopatología , Humanos , Lactante , Recién Nacido , Aminoacidurias Renales/fisiopatología , Sodio/metabolismoAsunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Aminoacidurias Renales/fisiopatología , Adolescente , Errores Innatos del Metabolismo de los Aminoácidos/clasificación , Aminoácidos/sangre , Aminoácidos/fisiología , Aminoácidos/orina , Transporte Biológico , Niño , Preescolar , Cistinosis/fisiopatología , Cistinuria/fisiopatología , Diuresis , Tasa de Filtración Glomerular , Humanos , Lactante , Pruebas de Función Renal , Glomérulos Renales/fisiología , Túbulos Renales/fisiología , Masculino , Fenilcetonurias/fisiopatología , Defectos Congénitos del Transporte Tubular Renal/clasificación , Defectos Congénitos del Transporte Tubular Renal/fisiopatologíaAsunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/genética , Antipsicóticos/efectos adversos , Discapacidad Intelectual/complicaciones , Aminoacidurias Renales/genética , Adolescente , Arginina/sangre , Arginina/orina , Clorpromazina/efectos adversos , Cistinuria , Femenino , Flufenazina/efectos adversos , Humanos , Absorción Intestinal , Túbulos Renales/fisiopatología , Lisina/sangre , Lisina/orina , Trastornos del Movimiento/inducido químicamente , Ornitina/sangre , Ornitina/orina , Linaje , Aminoacidurias Renales/fisiopatología , Tioridazina/efectos adversos , Trihexifenidilo/efectos adversosAsunto(s)
Riñón/metabolismo , Vitamina E/metabolismo , Animales , Isótopos de Carbono , Gatos , Bovinos , Esterasas/metabolismo , Femenino , Humanos , Riñón/enzimología , Riñón/patología , Riñón/fisiología , Masculino , Oxidación-Reducción , Fosforilación Oxidativa , Monoéster Fosfórico Hidrolasas/metabolismo , Embarazo , Conejos , Ratas , Aminoacidurias Renales/fisiopatología , Porcinos , Transaminasas/metabolismo , Pavos , Ubiquinona/metabolismo , Vitamina A/metabolismo , Deficiencia de Vitamina A/metabolismo , Deficiencia de Vitamina E/metabolismo , Deficiencia de Vitamina E/patologíaAsunto(s)
Aminoácidos/metabolismo , Absorción Intestinal , Escorbuto/metabolismo , Alanina/metabolismo , Aminoácidos/sangre , Aminoácidos/orina , Animales , Líquidos Corporales , Isótopos de Carbono , Glicina/sangre , Glicina/metabolismo , Glicina/orina , Cobayas , Técnicas In Vitro , Inulina , Yeyuno/fisiología , Lisina/metabolismo , Métodos , Aminoacidurias Renales/fisiopatologíaRESUMEN
A mutation affecting renal transport of proline, hydroxyproline, and glycerine occurs in man. In the presumed homozygote there is still significant residual transport of these compounds; however, this remaining function is saturated at normal concentrations of substrate in the plasma and is not inhibited by L-proline in the expected way. The presumed heterozygote has partial loss of a transport system common to the three substrates, which becomes saturated at high concentrations of substrate and is inhibited by L-proline. Two different types of transport systems are proposed: a common system and systems with lower capacity and greater specificity. The two types of transport appear to be controlled by separate genes.