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1.
Curr Opin Nephrol Hypertens ; 32(4): 359-365, 2023 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-37074688

RESUMEN

PURPOSE OF REVIEW: Most kidney stones are composed of calcium, and the greatest risk factor for kidney stone formation is hypercalciuria. Patients who form kidney stones often have reduced calcium reabsorption from the proximal tubule, and increasing this reabsorption is a goal of some dietary and pharmacological treatment strategies to prevent kidney stone recurrence. However, until recently, little was known about the molecular mechanism that mediates calcium reabsorption from the proximal tubule. This review summarizes newly uncovered key insights and discusses how they may inform the treatment of kidney stone formers. RECENT FINDINGS: Studies examining claudin-2 and claudin-12 single and double knockout mice, combined with cell culture models, support complementary independent roles for these tight junction proteins in contributing paracellular calcium permeability to the proximal tubule. Moreover, a family with a coding variation in claudin-2 causing hypercalciuria and kidney stones have been reported, and reanalysis of Genome Wide Association Study (GWAS) data demonstrates an association between noncoding variations in CLDN2 and kidney stone formation. SUMMARY: The current work begins to delineate the molecular mechanisms whereby calcium is reabsorbed from the proximal tubule and suggests a role for altered claudin-2 mediated calcium reabsorption in the pathogenesis of hypercalciuria and kidney stone formation.


Asunto(s)
Calcio , Hipercalciuria , Cálculos Renales , Cálculos Renales/genética , Cálculos Renales/fisiopatología , Cálculos Renales/prevención & control , Cálculos Renales/terapia , Hipercalciuria/genética , Hipercalciuria/fisiopatología , Hipercalciuria/prevención & control , Hipercalciuria/terapia , Calcio/metabolismo , Humanos , Animales , Claudina-2/genética , Claudina-2/metabolismo , Claudinas/genética , Claudinas/metabolismo , Estudio de Asociación del Genoma Completo , Túbulos Renales Proximales/fisiopatología
2.
BMC Endocr Disord ; 21(1): 170, 2021 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-34416890

RESUMEN

BACKGROUND: The occurrence of hypomagnesemia in patients with primary hyperparathyroidism (PHPT) has been noted previously; however, the association of hypomagnesemia and severity of primary hyperparathyroidism remains unknown. The present study aimed to evaluate the association of hypomagnesemia with biochemical and clinical manifestations in patients with PHPT. METHODS: This was a retrospective study conducted at a tertiary hospital. We obtained data from 307 patients with PHPT from January 2010 through August 2020. Data on demographics, history, laboratory findings, bone densitometry findings, and clinical presentation and complications were collected and were compared in normal magnesium group vs hypomagnesemia group. RESULTS: Among the 307 patients with PHPT included in our study, 77 patients (33/102 [32.4%] males and 44/205 [21.5%] females) had hypomagnesemia. Mean hemoglobin levels in the hypomagnesemia group were significantly lower than those in the normal magnesium group in both males and females. In contrast, patients with hypomagnesemia had a higher mean serum calcium and parathyroid hormone than individuals with normal magnesium. The typical symptoms of PHPT, such as nephrolithiasis, bone pain/fractures, polyuria, or polydipsia, were more common in the hypomagnesemia group. In addition, patients with hypomagnesemia had a higher prevalence of osteoporosis, anemia, and hypercalcemic crisis. Even after adjusting for potential confounders, including age, sex, body mass index, estimated glomerular filtration rate, and parathyroid hormone levels, these associations remained essentially unchanged. CONCLUSION: Biochemical and clinical evidence indicates that patients with PHPT with hypomagnesemia have more severe hyperparathyroidism than those without hypomagnesemia. In addition, PHPT patients with hypomagnesemia had a higher prevalence of osteoporosis, anemia, and hypercalcemic crisis.


Asunto(s)
Biomarcadores/sangre , Densidad Ósea , Hipercalciuria/fisiopatología , Hiperparatiroidismo Primario/patología , Nefrocalcinosis/fisiopatología , Osteoporosis/patología , Defectos Congénitos del Transporte Tubular Renal/fisiopatología , Calcio/sangre , Estudios de Casos y Controles , China/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Hipercalciuria/sangre , Hiperparatiroidismo Primario/sangre , Hiperparatiroidismo Primario/epidemiología , Masculino , Persona de Mediana Edad , Nefrocalcinosis/sangre , Osteoporosis/sangre , Osteoporosis/etiología , Hormona Paratiroidea/sangre , Pronóstico , Estudios Prospectivos , Defectos Congénitos del Transporte Tubular Renal/sangre
3.
Int J Mol Sci ; 22(7)2021 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-33808324

RESUMEN

Calcium (Ca2+) is an important mediator of multicellular homeostasis and is involved in several diseases. The interplay among the kidney, bone, intestine, and parathyroid gland in Ca2+ homeostasis is strictly modulated by numerous hormones and signaling pathways. The calcium-sensing receptor (CaSR) is a G protein-coupled receptor, that is expressed in calcitropic tissues such as the parathyroid gland and the kidney, plays a pivotal role in Ca2+ regulation. CaSR is important for renal Ca2+, as a mutation in this receptor leads to hypercalciuria and calcium nephrolithiasis. In addition, CaSR is also widely expressed in the vascular system, including vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) and participates in the process of vascular calcification. Aberrant Ca2+ sensing by the kidney and VSMCs, owing to altered CaSR expression or function, is associated with the formation of nephrolithiasis and vascular calcification. Based on emerging epidemiological evidence, patients with nephrolithiasis have a higher risk of vascular calcification, but the exact mechanism linking the two conditions is unclear. However, a dysregulation in Ca2+ homeostasis and dysfunction in CaSR might be the connection between the two. This review summarizes renal calcium handling and calcium signaling in the vascular system, with a special focus on the link between nephrolithiasis and vascular calcification.


Asunto(s)
Señalización del Calcio/fisiología , Nefrolitiasis/metabolismo , Calcificación Vascular/metabolismo , Animales , Calcio/metabolismo , Células Endoteliales/metabolismo , Humanos , Hipercalciuria/genética , Hipercalciuria/metabolismo , Hipercalciuria/fisiopatología , Riñón/metabolismo , Cálculos Renales/metabolismo , Miocitos del Músculo Liso/metabolismo , Nefrolitiasis/fisiopatología , Receptores Sensibles al Calcio/genética , Calcificación Vascular/genética , Calcificación Vascular/fisiopatología
5.
Mediators Inflamm ; 2020: 5785378, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33144848

RESUMEN

PURPOSE: Systemic mastocytosis (SM) is characterized by a clonal proliferation of neoplastic mast cells (MCs) in one or more extracutaneous organs including the bone marrow (BM). SM is often associated with osteoporosis (OP) and fractures. Hypertryptasemia usually occurs in SM. We investigated the prevalence of hypertryptasemia in a series of severe osteoporotic patients, the performance of the tryptase test in diagnosing SM in these patients, and their bone features. METHODS: The medical records of 232 patients (168 females and 64 males) with a diagnosis of OP (50.4% with fractures) and a serum tryptase assessment were reviewed. BM assessment was performed in a subset of hypertryptasemic patients; clinical, biochemical, and radiographic data were collected. RESULTS: Hypertryptasemia was detected in 33 patients. BM assessment (n = 16) was normal in 8 hypertryptasemic patients, while BM criteria for the diagnosis of SM were met in 3 patients, MC alterations were detected in 4 patients, and one patient presented a polycythemia vera. Serum tryptase levels were higher than 11.4 ng/ml in all patients with BM alterations. The best cut-off of tryptase level related to BM alterations was 17.9 ng/ml, with a sensibility and sensitivity of 75% (AUC = 0.797 and P = 0.015 by ROC analysis). All osteoporotic patients with hypertryptasemia experienced at least one vertebral fracture associated with a severe reduction of the lumbar bone mineral density. CONCLUSIONS: The prevalence of MC-related disorders in severe OP was 3.0%, accounting for the 7.4% of the secondary causes of OP. MC-related disorders may be involved in bone fragility and assessment of serum tryptase is useful to detect MC-related disorders.


Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Hipercalciuria/sangre , Hipercalciuria/fisiopatología , Mastocitos/patología , Mastocitosis Sistémica/patología , Adulto , Anciano , Errores Innatos del Metabolismo de los Aminoácidos/sangre , Médula Ósea/metabolismo , Médula Ósea/patología , Femenino , Humanos , Masculino , Mastocitosis Sistémica/sangre , Persona de Mediana Edad , Osteoporosis/sangre , Osteoporosis/fisiopatología , Triptasas/metabolismo
6.
BMC Nephrol ; 21(1): 171, 2020 05 11.
Artículo en Inglés | MEDLINE | ID: mdl-32393202

RESUMEN

BACKGROUND: Female Dent disease 1 patients with low-molecular-weight proteinuria (LMWP) due to CLCN5 gene mutation were rarely reported, and these cases that the people were also with Turner syndrome (TS) were even hardly documented before. CASE PRESENTATION: Here we report a 3-year and 11-month old Chinese girl with short stature who had a karyotype of 46,X,i(X)(q10) and a de novo pathogenic variant in the CLCN5 gene on the short arm of X chromosome. Laboratory examinations showed that the patient had LMWP, hypercalciuria, hypophosphatemia, delayed bone age, and genital dysplasia. CONCLUSION: The combination of i(X)(q10) and CLCN5 mutation causes the deletion of the wild-type CLCN5 allele that results in Dent-1 and TS. To the best of our knowledge, this is the first case that a female CLCN5 mutation hemizygote is diagnosed with Dent-1 and Turner syndrome due to isochromosome X. Also, our case has indicated that the prevalence of the situation may be largely underestimated because of the mild signs of females with Dent-1.


Asunto(s)
Canales de Cloruro/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Nefrolitiasis/genética , Síndrome de Turner/genética , Desarrollo Óseo , Huesos/diagnóstico por imagen , Preescolar , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/complicaciones , Enfermedades Genéticas Ligadas al Cromosoma X/fisiopatología , Hemicigoto , Humanos , Hipercalciuria/fisiopatología , Hipofosfatemia/fisiopatología , Isocromosomas , Riñón/diagnóstico por imagen , Mutación , Nefrolitiasis/complicaciones , Nefrolitiasis/fisiopatología , Ovario/anomalías , Ovario/diagnóstico por imagen , Proteinuria/fisiopatología , Síndrome de Turner/complicaciones , Síndrome de Turner/fisiopatología , Útero/anomalías , Útero/diagnóstico por imagen
7.
Am J Physiol Renal Physiol ; 318(2): F363-F374, 2020 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-31790303

RESUMEN

In stone formers (SFs) with idiopathic hypercalciuria, urine pH governs the mineral phase of stones. Calcium phosphate (CaP) SFs have higher urine pH than calcium oxalate (CaOx) SFs. Normal women have higher urine pH than men on fixed diets, accompanied by greater absorption of food alkali. Female CaP and male CaOx SFs have similar urine pH as same sex normal individuals, but male CaP and female CaOx SFs may have abnormal acid-base handling. We studied 25 normal individuals (13 men and 12 women), 17 CaOx SFs (11 men and 6 women), and 15 CaP SFs (8 men and 7 women) on fixed diets. Urine and blood samples were collected under fasting and fed conditions. Female CaOx SFs had lower urine pH and lower alkali absorption, fed, compared with normal women; their urine NH4 was higher and urine citrate excretion lower than in normal women, consistent with their higher net acid excretion. Male CaOx SFs had higher urine citrate excretion and higher serum ultrafilterable citrate levels than normal men. Both male and female CaP SFs had higher urine pH fasting than same sex normal individuals, but only men were higher in the fed period, and there were no differences from normal in gut alkali absorption. CaP SFs of both sexes had higher urine NH4 and lower urine citrate than same sex normal individuals. The lower urine pH of female CaOx SFs seems related to decreased gut alkali absorption, while the higher pH of CaP SFs, accompanied by higher urine NH4 and lower urine citrate, suggests a proximal tubule disorder.


Asunto(s)
Equilibrio Ácido-Base , Desequilibrio Ácido-Base/orina , Oxalato de Calcio/orina , Fosfatos de Calcio/orina , Hipercalciuria/orina , Cálculos Renales/orina , Túbulos Renales Proximales/metabolismo , Desequilibrio Ácido-Base/sangre , Desequilibrio Ácido-Base/diagnóstico , Desequilibrio Ácido-Base/fisiopatología , Adulto , Compuestos de Amonio/orina , Biomarcadores/sangre , Biomarcadores/orina , Estudios de Casos y Controles , Ácido Cítrico/orina , Cristalización , Dieta/efectos adversos , Femenino , Absorción Gastrointestinal , Humanos , Concentración de Iones de Hidrógeno , Hipercalciuria/sangre , Hipercalciuria/diagnóstico , Hipercalciuria/fisiopatología , Cálculos Renales/sangre , Cálculos Renales/diagnóstico , Cálculos Renales/fisiopatología , Túbulos Renales Proximales/fisiopatología , Masculino , Persona de Mediana Edad , Factores de Riesgo , Factores Sexuales , Adulto Joven
8.
Am J Physiol Renal Physiol ; 316(5): F966-F969, 2019 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-30838875

RESUMEN

The proximal tubule (PT) is responsible for the majority of calcium reabsorption by the kidney. Most PT calcium transport appears to be passive, although the molecular facilitators have not been well established. Emerging evidence supports a major role for PT calcium transport in idiopathic hypercalciuria and the development of kidney stones. This review will cover recent developments in our understanding of PT calcium transport and the role of the PT in kidney stone formation.


Asunto(s)
Calcio/metabolismo , Hipercalciuria/complicaciones , Cálculos Renales/etiología , Túbulos Renales Proximales/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Nefrocalcinosis/etiología , Reabsorción Renal , Animales , Claudinas/metabolismo , Humanos , Hipercalciuria/metabolismo , Hipercalciuria/fisiopatología , Transporte Iónico , Cálculos Renales/metabolismo , Cálculos Renales/fisiopatología , Túbulos Renales Proximales/fisiopatología , Nefrocalcinosis/metabolismo , Nefrocalcinosis/fisiopatología
9.
Nat Rev Endocrinol ; 15(1): 33-51, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30443043

RESUMEN

The Ca2+-sensing receptor (CaSR) is a dimeric family C G protein-coupled receptor that is expressed in calcitropic tissues such as the parathyroid glands and the kidneys and signals via G proteins and ß-arrestin. The CaSR has a pivotal role in bone and mineral metabolism, as it regulates parathyroid hormone secretion, urinary Ca2+ excretion, skeletal development and lactation. The importance of the CaSR for these calcitropic processes is highlighted by loss-of-function and gain-of-function CaSR mutations that cause familial hypocalciuric hypercalcaemia and autosomal dominant hypocalcaemia, respectively, and also by the fact that alterations in parathyroid CaSR expression contribute to the pathogenesis of primary and secondary hyperparathyroidism. Moreover, the CaSR is an established therapeutic target for hyperparathyroid disorders. The CaSR is also expressed in organs not involved in Ca2+ homeostasis: it has noncalcitropic roles in lung and neuronal development, vascular tone, gastrointestinal nutrient sensing, wound healing and secretion of insulin and enteroendocrine hormones. Furthermore, the abnormal expression or function of the CaSR is implicated in cardiovascular and neurological diseases, as well as in asthma, and the CaSR is reported to protect against colorectal cancer and neuroblastoma but increase the malignant potential of prostate and breast cancers.


Asunto(s)
Calcimiméticos/uso terapéutico , Hipercalcemia/congénito , Hipercalciuria/genética , Hipocalcemia/genética , Hipoparatiroidismo/congénito , Nefrolitiasis/genética , Receptores Sensibles al Calcio/genética , Femenino , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad/epidemiología , Humanos , Hipercalcemia/tratamiento farmacológico , Hipercalcemia/genética , Hipercalcemia/fisiopatología , Hipercalciuria/tratamiento farmacológico , Hipercalciuria/fisiopatología , Hipocalcemia/tratamiento farmacológico , Hipocalcemia/fisiopatología , Hipoparatiroidismo/tratamiento farmacológico , Hipoparatiroidismo/genética , Hipoparatiroidismo/fisiopatología , Incidencia , Masculino , Mutación/genética , Nefrolitiasis/tratamiento farmacológico , Nefrolitiasis/fisiopatología , Pronóstico , Receptores Sensibles al Calcio/efectos de los fármacos , Medición de Riesgo , Resultado del Tratamiento
10.
Sci Signal ; 11(518)2018 02 20.
Artículo en Inglés | MEDLINE | ID: mdl-29463778

RESUMEN

The calcium-sensing receptor (CaSR) is a G protein-coupled receptor (GPCR) that signals through Gq/11 and Gi/o to stimulate cytosolic calcium (Ca2+i) and mitogen-activated protein kinase (MAPK) signaling to control extracellular calcium homeostasis. Studies of loss- and gain-of-function CASR mutations, which cause familial hypocalciuric hypercalcemia type 1 (FHH1) and autosomal dominant hypocalcemia type 1 (ADH1), respectively, have revealed that the CaSR signals in a biased manner. Thus, some mutations associated with FHH1 lead to signaling predominantly through the MAPK pathway, whereas mutations associated with ADH1 preferentially enhance Ca2+i responses. We report a previously unidentified ADH1-associated R680G CaSR mutation, which led to the identification of a CaSR structural motif that mediates biased signaling. Expressing CaSRR680G in HEK 293 cells showed that this mutation increased MAPK signaling without altering Ca2+i responses. Moreover, this gain of function in MAPK activity occurred independently of Gq/11 and Gi/o and was mediated instead by a noncanonical pathway involving ß-arrestin proteins. Homology modeling and mutagenesis studies showed that the R680G CaSR mutation selectively enhanced ß-arrestin signaling by disrupting a salt bridge formed between Arg680 and Glu767, which are located in CaSR transmembrane domain 3 and extracellular loop 2, respectively. Thus, our results demonstrate CaSR signaling through ß-arrestin and the importance of the Arg680-Glu767 salt bridge in mediating signaling bias.


Asunto(s)
Membrana Celular/metabolismo , Hipercalciuria/fisiopatología , Hipocalcemia/fisiopatología , Hipoparatiroidismo/congénito , Sistema de Señalización de MAP Quinasas , Mutación , Receptores Sensibles al Calcio/metabolismo , Sales (Química)/metabolismo , beta-Arrestinas/metabolismo , Secuencia de Aminoácidos , Secuencia de Bases , Calcio/metabolismo , Membrana Celular/química , Salud de la Familia , Femenino , Humanos , Hipercalciuria/genética , Hipocalcemia/genética , Hipoparatiroidismo/genética , Hipoparatiroidismo/fisiopatología , Masculino , Modelos Moleculares , Linaje , Conformación Proteica , Receptores Sensibles al Calcio/química , Receptores Sensibles al Calcio/genética , Sales (Química)/química , Homología de Secuencia de Aminoácido
11.
Kidney Int ; 93(3): 580-588, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29129401

RESUMEN

The tight junction proteins claudin-10 and -16 are crucial for the paracellular reabsorption of cations along the thick ascending limb of Henle's loop in the kidney. In patients, mutations in CLDN16 cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis, while mutations in CLDN10 impair kidney function. Mice lacking claudin-16 display magnesium and calcium wasting, whereas absence of claudin-10 results in hypermagnesemia and interstitial nephrocalcinosis. In order to study the functional interdependence of claudin-10 and -16 we generated double-deficient mice. These mice had normal serum magnesium and urinary excretion of magnesium and calcium and showed polyuria and sodium retention at the expense of increased renal potassium excretion, but no nephrocalcinosis. Isolated thick ascending limb tubules of double mutants displayed a complete loss of paracellular cation selectivity and functionality. Mice lacking both claudin-10 and -16 in the thick ascending limb recruited downstream compensatory mechanisms and showed hypertrophic distal convoluted tubules with changes in gene expression and phosphorylation of ion transporters in this segment, presumably triggered by the mild decrease in serum potassium. Thus, severe individual phenotypes in claudin-10 and claudin-16 knockout mice are corrected by the additional deletion of the other claudin.


Asunto(s)
Claudinas/deficiencia , Hipercalciuria/prevención & control , Túbulos Renales Distales/metabolismo , Asa de la Nefrona/metabolismo , Deficiencia de Magnesio/prevención & control , Animales , Calcio/metabolismo , Claudinas/genética , Modelos Animales de Enfermedad , Eliminación de Gen , Predisposición Genética a la Enfermedad , Hipercalciuria/genética , Hipercalciuria/metabolismo , Hipercalciuria/fisiopatología , Túbulos Renales Distales/patología , Túbulos Renales Distales/fisiopatología , Asa de la Nefrona/patología , Asa de la Nefrona/fisiopatología , Magnesio/metabolismo , Deficiencia de Magnesio/genética , Deficiencia de Magnesio/metabolismo , Deficiencia de Magnesio/fisiopatología , Ratones Endogámicos C57BL , Ratones Noqueados , Nefrocalcinosis/genética , Nefrocalcinosis/metabolismo , Nefrocalcinosis/fisiopatología , Nefrocalcinosis/prevención & control , Fenotipo , Sodio/metabolismo
13.
Iran J Kidney Dis ; 11(3): 180-191, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28575878

RESUMEN

The pathophysiology of urinary stone formation is complex, involving a combination of metabolic, genetic, and environmental factors. Over the past decades, remarkable advances have been emerged in the understanding of the pathogenesis, diagnosis, and treatment of calcium kidney calculi. For this review, both original and review articles were found via PubMed search on pathophysiology, diagnosis, and management of urinary calculi. These resources were integrated with the authors' knowledge of the field. Nephrolithiasis is suggested to be associated with systemic disorders, including chronic kidney insufficiency, hematologic malignancies, endocrine disorders, autoimmune diseases, inflammatory bowel diseases, bone loss and fractures, hypertension, type 2 diabetes mellitus, metabolic syndrome, and vascular diseases like coronary heart diseases and most recently ischemic strokes. This is changing the perspective of nephrolithiasis from an isolated disorder to a systemic disease that justifies further research in understanding the underlying mechanisms and elaborating diagnostic-therapeutic options.


Asunto(s)
Hipercalciuria , Cálculos Renales , Riñón , Animales , Humanos , Hipercalciuria/diagnóstico , Hipercalciuria/epidemiología , Hipercalciuria/fisiopatología , Hipercalciuria/terapia , Riñón/fisiopatología , Cálculos Renales/diagnóstico , Cálculos Renales/epidemiología , Cálculos Renales/fisiopatología , Cálculos Renales/terapia , Pronóstico , Factores de Riesgo
14.
Kidney Int ; 91(4): 842-855, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-28143656

RESUMEN

Dent disease is a rare X-linked tubulopathy caused by mutations in the endosomal chloride-proton exchanger (ClC-5) resulting in defective receptor-mediated endocytosis and severe proximal tubule dysfunction. Bone marrow transplantation has recently been shown to preserve kidney function in cystinosis, a lysosomal storage disease causing proximal tubule dysfunction. Here we test the effects of bone marrow transplantation in Clcn5Y/- mice, a faithful model for Dent disease. Transplantation of wild-type bone marrow in Clcn5Y/- mice significantly improved proximal tubule dysfunction, with decreased low-molecular-weight proteinuria, glycosuria, calciuria, and polyuria four months after transplantation, compared to Clcn5Y/- mice transplanted with ClC-5 knockout bone marrow. Bone marrow-derived cells engrafted in the interstitium, surrounding proximal tubule cells, which showed a rescue of the apical expression of ClC-5 and megalin receptors. The improvement of proximal tubule dysfunction correlated with Clcn5 gene expression in kidneys of mice transplanted with wild-type bone marrow cells. Coculture of Clcn5Y/- proximal tubule cells with bone marrow-derived cells confirmed rescue of ClC-5 and megalin, resulting in improved endocytosis. Nanotubular extensions between the engrafted bone marrow-derived cells and proximal tubule cells were observed in vivo and in vitro. No rescue was found when the formation of the tunneling nanotubes was prevented by actin depolymerization or when cells were physically separated by transwell inserts. Thus, bone marrow transplantation may rescue the epithelial phenotype due to an inherited endosomal defect. Direct contacts between bone marrow-derived cells and diseased tubular cells play a key role in the rescue mechanism.


Asunto(s)
Trasplante de Médula Ósea , Canales de Cloruro/deficiencia , Enfermedad de Dent/cirugía , Túbulos Renales Proximales/fisiopatología , Animales , Comunicación Celular , Células Cultivadas , Canales de Cloruro/genética , Técnicas de Cocultivo , Enfermedad de Dent/genética , Enfermedad de Dent/metabolismo , Enfermedad de Dent/fisiopatología , Modelos Animales de Enfermedad , Endocitosis , Predisposición Genética a la Enfermedad , Glucosuria/genética , Glucosuria/metabolismo , Glucosuria/fisiopatología , Glucosuria/prevención & control , Hipercalciuria/genética , Hipercalciuria/metabolismo , Hipercalciuria/fisiopatología , Hipercalciuria/prevención & control , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/patología , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Poliuria/genética , Poliuria/metabolismo , Poliuria/fisiopatología , Poliuria/prevención & control , Proteinuria/genética , Proteinuria/metabolismo , Proteinuria/fisiopatología , Proteinuria/prevención & control , Recuperación de la Función , Quimera por Trasplante
15.
Nefrología (Madr.) ; 37(1): 5-8, ene.-feb. 2017. ilus
Artículo en Español | IBECS | ID: ibc-160592

RESUMEN

La reabsorción tubular de calcio es uno de los principales factores que determinan la concentración sérica de calcio y su excreción urinaria. El túbulo contorneado distal y conector es donde se produce la regulación fina de la calciuria. A ese nivel se encuentra el canal epitelial de Ca (TRPV5), que es el paso limitante en el transporte transcelular de Ca. La presencia dinámica del canal TRPV5 en la superficie de la célula tubular está mediada por un proceso de reciclado endosómico. Distintos factores intrarrenales intervienen en la fijación del canal de calcio en la membrana aplical, entre ellos la hormona antienvejecimiento klotho y la calicreína tisular (CT). Ambas proteínas son sintetizadas en el túbulo distal y secretadas en el fluido tubular. La calicreína tisular estimula la reabsorción activa de calcio por vía del receptor de bradiquinina tipo 2 que compromete la activación del of TRPV5 por vía de la protein cinasa C. Los ratones deficientes en CT muestran hipercalciuria de origen renal comparable a la pérdida de calcio que se observa en los ratones knockout para el TRPV5. Existe un polimorfismo con pérdida de función del gen de la CT humana denominado R53H (alelo H) que produce una gran disminución de la actividad enzimática. La presencia del alelo H, por lo menos en la población japonesa, parece ser frecuente (24%). Estos individuos tiene una tendencia a excreción más alta de calcio y sodio en orina que se manifiesta más durante la infusión de furosemida. En el futuro habrá que estudiar si la manipulación del sistema calicreína-quinina renal permite corregir la hipercalciuria idiopática con fármacos diferentes a los diuréticos tiazídicos (AU)


Renal tubular calcium reabsorption is one of the principal factors that determine serum calcium concentration and calcium excretion. Calcium excretion is regulated by the distal convoluted tubule and connecting tubule, where the epithelial calcium channel TRPV5 can be found, which limits the rate of transcellular calcium transport. The dynamic presence of the TRPV5 channel on the surface of the tubular cell is mediated by an endosomal recycling process. Different intrarenal factors are involved in calcium channel fixation in the apical membrane, including the anti-ageing hormone klotho and tissue kallikrein (TK). Both proteins are synthesised in the distal tubule and secreted in the tubular fluid. TK stimulates active calcium reabsorption through the bradykinin receptor B2 that compromises TRPV5 activation through the protein kinase C pathway. TK-deficient mice show hypercalciuria of renal origin comparable to that seen in TRPV5 knockout mice. There is a polymorphism with loss of function of the human TK gene R53H (allele H) that causes a marked decrease in enzymatic activity. The presence of the allele H seems to be common at least in the Japanese population (24%). These individuals have a tendency to greater calcium and sodium excretion in urine that is more evident during furosemide infusion. Future studies should analyse if manipulating the renal kallikrein-kinin system can correct idiopathic hypercalciuria with drugs other than thiazide diuretics (AU)


Asunto(s)
Humanos , Sistema Calicreína-Quinina/fisiología , Hipercalciuria/fisiopatología , Calcio/metabolismo , Reabsorción Renal/fisiología
16.
Orphanet J Rare Dis ; 12(1): 19, 2017 01 25.
Artículo en Inglés | MEDLINE | ID: mdl-28122587

RESUMEN

The calcium-sensing receptor (CaSR) plays a pivotal role in systemic calcium metabolism by regulating parathyroid hormone secretion and urinary calcium excretion. The diseases caused by an abnormality of the CaSR are genetically determined or are more rarely acquired. The genetic diseases consist of hyper- or hypocalcemia disorders. Hypercalcaemia disorders are related to inactivating mutations of the CASR gene either heterozygous (autosomal dominant familial benign hypercalcaemia, still named hypocalciuric hypercalcaemia syndrome type 1) or homozygous (severe neonatal hyperparathyroidism). The A986S, R990G and Q1011E variants of the CASR gene are associated with higher serum calcium levels than in the general population, hypercalciuria being also associated with the R990G variant. The differential diagnosis consists in the hypocalciuric hypercalcaemia syndrome, types 2 (involving GNA11 gene) and 3 (involving AP2S1 gene); hyperparathyroidism; abnormalities of vitamin D metabolism, involving CYP24A1 and SLC34A1 genes; and reduced GFR. Hypocalcemia disorders, which are more rare, are related to heterozygous activating mutations of the CASR gene (type 1), consisting of autosomal dominant hypocalcemia disorders, sometimes with a presentation of pseudo-Bartter's syndrome. The differential diagnosis consists of the hypercalciuric hypocalcaemia syndrome type 2, involving GNA11 gene and other hypoparathyroidism aetiologies. The acquired diseases are related to the presence of anti-CaSR antibodies, which can cause hyper- or especially hypocalcemia disorders (for instance in APECED syndromes), determined by their functionality. Finally, the role of CaSR in digestive, respiratory, cardiovascular and neoplastic diseases is gradually coming to light, providing new therapeutic possibilities. Two types of CaSR modulators are known: CaSR agonists (or activators, still named calcimimetics) and calcilytic antagonists (or inhibitors of the CasR). CaSR agonists, such as cinacalcet, are indicated in secondary and primary hyperparathyroidism. Calcilytics have no efficacy in osteoporosis, but could be useful in the treatment of hypercalciuric hypocalcaemia syndromes.


Asunto(s)
Enfermedades Genéticas Congénitas/fisiopatología , Receptores Sensibles al Calcio/metabolismo , Animales , Calcio/sangre , Calcio/metabolismo , Subunidades alfa de la Proteína de Unión al GTP/genética , Subunidades alfa de la Proteína de Unión al GTP/metabolismo , Enfermedades Genéticas Congénitas/sangre , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/orina , Humanos , Hipercalciuria/sangre , Hipercalciuria/genética , Hipercalciuria/metabolismo , Hipercalciuria/fisiopatología , Hiperparatiroidismo/sangre , Hiperparatiroidismo/genética , Hiperparatiroidismo/fisiopatología , Receptores Sensibles al Calcio/genética
17.
Physiology (Bethesda) ; 30(4): 317-26, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-26136545

RESUMEN

In addition to its prominent role in the parathyroid gland, the calcium-sensing receptor (CaSR) is expressed in various tissues, including the kidney. This article reviews current data on the calcium-sensing properties of the kidney, the localization of the CaSR protein along the nephron, and its function in calcium homeostasis and in hypercalciuria.


Asunto(s)
Calcio/metabolismo , Túbulos Renales/metabolismo , Receptores Sensibles al Calcio/metabolismo , Animales , Homeostasis , Humanos , Hipercalciuria/metabolismo , Hipercalciuria/fisiopatología , Túbulos Renales/fisiopatología , Transducción de Señal
18.
J Bone Miner Res ; 30(11): 1980-93, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25967373

RESUMEN

Activating mutations of calcium-sensing receptor (CaSR) cause autosomal dominant hypocalcemia (ADH). ADH patients develop hypocalcemia, hyperphosphatemia, and hypercalciuria, similar to the clinical features of hypoparathyroidism. The current treatment of ADH is similar to the other forms of hypoparathyroidism, using active vitamin D3 or parathyroid hormone (PTH). However, these treatments aggravate hypercalciuria and renal calcification. Thus, new therapeutic strategies for ADH are needed. Calcilytics are allosteric antagonists of CaSR, and may be effective for the treatment of ADH caused by activating mutations of CaSR. In order to examine the effect of calcilytic JTT-305/MK-5442 on CaSR harboring activating mutations in the extracellular and transmembrane domains in vitro, we first transfected a mutated CaSR gene into HEK cells. JTT-305/MK-5442 suppressed the hypersensitivity to extracellular Ca(2+) of HEK cells transfected with the CaSR gene with activating mutations in the extracellular and transmembrane domains. We then selected two activating mutations locating in the extracellular (C129S) and transmembrane (A843E) domains, and generated two strains of CaSR knock-in mice to build an ADH mouse model. Both mutant mice mimicked almost all the clinical features of human ADH. JTT-305/MK-5442 treatment in vivo increased urinary cAMP excretion, improved serum and urinary calcium and phosphate levels by stimulating endogenous PTH secretion, and prevented renal calcification. In contrast, PTH(1-34) treatment normalized serum calcium and phosphate but could not reduce hypercalciuria or renal calcification. CaSR knock-in mice exhibited low bone turnover due to the deficiency of PTH, and JTT-305/MK-5442 as well as PTH(1-34) increased bone turnover and bone mineral density (BMD) in these mice. These results demonstrate that calcilytics can reverse almost all the phenotypes of ADH including hypercalciuria and renal calcification, and suggest that calcilytics can become a novel therapeutic agent for ADH.


Asunto(s)
Benzoatos/uso terapéutico , Hipercalciuria/tratamiento farmacológico , Hipercalciuria/genética , Hipocalcemia/tratamiento farmacológico , Hipocalcemia/genética , Hipoparatiroidismo/congénito , Mutación/genética , Propanolaminas/uso terapéutico , Receptores Sensibles al Calcio/genética , Animales , Secuencia de Bases , Benzoatos/farmacología , Remodelación Ósea/efectos de los fármacos , Huesos/efectos de los fármacos , Huesos/patología , Calcio/metabolismo , Modelos Animales de Enfermedad , Factor-23 de Crecimiento de Fibroblastos , Técnicas de Sustitución del Gen , Células HEK293 , Humanos , Hipercalciuria/patología , Hipercalciuria/fisiopatología , Hipocalcemia/patología , Hipocalcemia/fisiopatología , Hipoparatiroidismo/tratamiento farmacológico , Hipoparatiroidismo/genética , Hipoparatiroidismo/patología , Hipoparatiroidismo/fisiopatología , Ratones , Datos de Secuencia Molecular , Proteínas Mutantes/metabolismo , Tamaño de los Órganos/efectos de los fármacos , Fenotipo , Propanolaminas/farmacología
19.
Am J Physiol Regul Integr Comp Physiol ; 309(1): R85-92, 2015 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-25947170

RESUMEN

Idiopathic hypercalciuria (IH) is a common familial trait among patients with calcium nephrolithiasis. Previously, we have demonstrated that hypercalciuria is primarily due to reduced renal proximal and distal tubule calcium reabsorption. Here, using measurements of the clearances of sodium, calcium, and endogenous lithium taken from the General Clinical Research Center, we test the hypothesis that patterns of segmental nephron tubule calcium reabsorption differ between the sexes in IH and normal subjects. When the sexes are compared, we reconfirm the reduced proximal and distal calcium reabsorption. In IH women, distal nephron calcium reabsorption is decreased compared to normal women. In IH men, proximal tubule calcium reabsorption falls significantly, with a more modest reduction in distal calcium reabsorption compared to normal men. Additionally, we demonstrate that male IH patients have lower systolic blood pressures than normal males. We conclude that women and men differ in the way they produce the hypercalciuria of IH, with females reducing distal reabsorption and males primarily reducing proximal tubule function.


Asunto(s)
Calcio/orina , Hipercalciuria/metabolismo , Cálculos Renales/metabolismo , Túbulos Renales Distales/metabolismo , Túbulos Renales Proximales/metabolismo , Reabsorción Renal , Adulto , Anciano , Presión Sanguínea , Estudios de Casos y Controles , Ayuno/orina , Femenino , Humanos , Hipercalciuria/fisiopatología , Hipercalciuria/orina , Cálculos Renales/fisiopatología , Cálculos Renales/orina , Túbulos Renales Distales/fisiopatología , Túbulos Renales Proximales/fisiopatología , Magnesio/orina , Masculino , Persona de Mediana Edad , Modelos Biológicos , Periodo Posprandial , Factores Sexuales , Sodio/orina , Factores de Tiempo , Adulto Joven
20.
Ren Fail ; 37(1): 180-3, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25366522

RESUMEN

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is a rare autosomal recessive renal disease caused by mutations in genes for the tight junction transmembrane proteins Claudin-16 (CLDN16) and Claudin-19 (CLDN19). We present the first case report of a Mexican family with three affected sisters carrying a p.Gly20Asp mutation in CLDN19 whose heterozygous mother showed evident hypercalciuria and normal low magnesemia without any other clinical, laboratory, and radiological symptoms of renal disease making of her an unsuitable donor. The affected sisters showed variable phenotypic expression including age of first symptoms, renal urinary tract infections, nephrolithiasis, nephrocalcinosis, and eye symptoms consisting in retinochoroiditis, strabismus, macular scars, bilateral anisocoria, and severe myopia and astigmatism. End stage renal disease due to renal failure needed kidney transplantation in the three of them. Interesting findings were a heterozygous mother with asymptomatic hypercalciuria warning on the need of carefully explore clinical, laboratory, kidney ultrasonograpy, and mutation status in first degree asymptomatic relatives to avoid inappropriate kidney donors; an evident variable phenotypic expression among patients; the identification of a mutation almost confined to Spanish cases and a 3.5 Mb block of genomic homozygosis strongly suggesting a common remote parental ancestor for the gene mutation reported.


Asunto(s)
Claudinas/genética , Hipercalciuria , Fallo Renal Crónico , Nefrocalcinosis , Defectos Congénitos del Transporte Tubular Renal , Adulto , Femenino , Tamización de Portadores Genéticos , Humanos , Hipercalciuria/complicaciones , Hipercalciuria/diagnóstico , Hipercalciuria/etnología , Hipercalciuria/genética , Hipercalciuria/fisiopatología , Fallo Renal Crónico/etiología , Fallo Renal Crónico/cirugía , Trasplante de Riñón , México , Persona de Mediana Edad , Mutación , Nefrocalcinosis/complicaciones , Nefrocalcinosis/diagnóstico , Nefrocalcinosis/etnología , Nefrocalcinosis/genética , Nefrocalcinosis/fisiopatología , Linaje , Defectos Congénitos del Transporte Tubular Renal/complicaciones , Defectos Congénitos del Transporte Tubular Renal/diagnóstico , Defectos Congénitos del Transporte Tubular Renal/etnología , Defectos Congénitos del Transporte Tubular Renal/genética , Defectos Congénitos del Transporte Tubular Renal/fisiopatología
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