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1.
Life (Basel) ; 13(9)2023 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-37763221

RESUMEN

ADPKD is the most common genetic renal disease, characterized by the presence of multiple cysts which, through slow and gradual growth, lead to glomerular filtration rate (GFR) decline and end-stage renal disease. Cystic growth is associated with increased intracellular levels of 3',5'-cyclic adenosine monophosphate (cAMP). Extracellular vesicles (EVs) are proposed to participate in "remote sensing" by transporting different cargoes, but their relevance to ADPKD progression is poorly understood. This study aimed to determine whether cAMP is contained in urinary EVs and, if so, how total and/or EV cAMP contents participate in disease progression. Fourteen ADPKD patients, naïve for V2 receptor antagonism treatment, and seven controls were studied. Progression was evaluated by estimating GFR (eGFR) and height-adjusted total kidney volume (htTKV). Fresh morning urine was collected to determine cAMP by the competitive radioligand assay. Urine EVs were isolated using an adapted centrifugation method and characterized by electron microscopy, dynamic light scanning, flow cytometry with FITC CD63 labeling, protein and RNA content, and AQP2 and GAPDH mRNA detection. Total and EV cAMP was measurable in both control and patient urine samples. Total cAMP was significantly correlated with eGFR and its annual change but inversely correlated with htTKV. The cAMP-EVs showed a bimodal pattern with htTKV, increasing to ~1 L/m and falling at larger sizes. Our results demonstrate that urine cAMP correlates with ADPKD progression markers, and that its extracellular delivery by EVs could reflect the architectural disturbances of the organ.

2.
Nephron ; 140(4): 282-288, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30368514

RESUMEN

The calcium signalling and hedgehog (HH) signalling pathways operate in the primary cilium. Abnormalities in these pathways cause autosomal dominant polycystic kidney disease (ADPKD) and naevoid basal cell carcinoma syndrome (NBCCS) respectively. Several reports have proposed that hyperactivation of the HH pathway in animal models of polycystic kidney disease affects normal renal development and renal cyst phenotype. A family with 2 cases (a proband and her sister) of ADPKD and NBCCS coinheritance led us to investigate whether interactions may be present in the 2 pathways. The effect of HH pathway hyperactivation (due to c.573C>G mutation on PTCH1 gene that cause NBCCS) on renal ADPKD progression in the proband was compared to 18 age- and sex-matched ADPKD patients in a 9-year, prospective, follow-up study. Blood pressure, total kidney volume, estimated glomerular filtration rate, plasma copeptin, urine excretion of albumin, total protein and monocyte chemoattractant protein-1 (MCP-1) were analysed. Data for the sibling was not available. In the ADPKD group, blood pressure and estimated glomerular filtration rate were within normal values, and total kidney volume and MCP-1 increased (p < 0.01) throughout the study. In comparison, during the 9-year follow-up, the proband showed persistent hypertension (from 125/85 to 140/95 mm Hg), low total kidney volume (75 and 61% of median ADPKD), and a ninefold increase in urine MCP-1. We found no differences in urine excretion of albumin or plasma copeptin values. These results suggest that HH hyperactivation may play a minimal role in ADPKD progression. These observations can help to clarify the clinical impact of affected pathways in renal development and cystogenesis in humans.


Asunto(s)
Síndrome del Nevo Basocelular/complicaciones , Síndrome del Nevo Basocelular/genética , Riñón Poliquístico Autosómico Dominante/complicaciones , Riñón Poliquístico Autosómico Dominante/genética , Adulto , Presión Sanguínea , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Proteínas Hedgehog/genética , Humanos , Pruebas de Función Renal , Receptor Patched-1/genética , Linaje , Estudios Prospectivos , Diálisis Renal , Transducción de Señal/genética
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