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1.
Nephrol Dial Transplant ; 35(2): 250-264, 2020 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-31411705

RESUMEN

BACKGROUND: Cardiorenal syndrome is a major cause of mortality in patients with chronic kidney disease (CKD). However, the involvement of detrimental humoral mediators in the pathogenesis of cardiorenal syndrome is still controversial. Trimethylamine-N-oxide (TMAO), a hepatic metabolic product of trimethylamine generated from dietary phosphatidylcholine or carnitine derived by the gut microbiota, has been linked directly with progression of cardiovascular disease and renal dysfunction. Thus, targeting TMAO may be a novel strategy for the prevention of cardiovascular disease and chronic kidney disease. METHODS: Linaclotide, a guanylate cyclase C agonist, was administered to adenine-induced renal failure (RF) mice and changes in renal function and levels of gut-derived uremic toxins, as well as the gut microbiota community, were analyzed using metabolomic and metagenomic methods to reveal its cardiorenal effect. RESULTS: Linaclotide decreased the plasma levels of TMAO at a clinically used low dose of 10 µg/kg in the adenine-induced RF mouse model. At a high concentration of 100 µg/kg, linaclotide clearly improved renal function and reduced the levels of various uremic toxins. A reduction in TMAO levels following linaclotide treatment was also observed in a choline-fed pro-atherosclerotic model. Linaclotide ameliorated renal inflammation and fibrosis and cardiac fibrosis, as well as decreased the expression of collagen I, transforming growth factor-ß, galectin-3 (Gal-3) and ST2 genes. Plasma levels of Gal-3 and ST2 were also reduced. Because exposure of cardiomyocytes to TMAO increased fibronectin expression, these data suggest that linaclotide reduced the levels of TMAO and various uremic toxins and may result in not only renal, but also cardiac, fibrosis. F4/80-positive macrophages were abundant in small intestinal crypts in RF mice, and this increased expression was decreased by linaclotide. Reduced colonic claudin-1 levels were also restored by linaclotide, suggesting that linaclotide ameliorated the 'leaky gut' in RF mice. Metagenomic analysis revealed that the microbial order Clostridiales could be responsible for the change in TMAO levels. CONCLUSION: Linaclotide reduced TMAO and uremic toxin levels and could be a powerful tool for the prevention and control of the cardiorenal syndrome by modification of the gut-cardio-renal axis.


Asunto(s)
Adenina/toxicidad , Síndrome Cardiorrenal/tratamiento farmacológico , Microbioma Gastrointestinal/efectos de los fármacos , Guanilato Ciclasa/química , Agonistas de la Guanilato Ciclasa C/farmacología , Péptidos/farmacología , Insuficiencia Renal Crónica/tratamiento farmacológico , Animales , Síndrome Cardiorrenal/inducido químicamente , Síndrome Cardiorrenal/metabolismo , Síndrome Cardiorrenal/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Fibrosis/inducido químicamente , Fibrosis/tratamiento farmacológico , Fibrosis/metabolismo , Fibrosis/patología , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Insuficiencia Renal Crónica/inducido químicamente , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología
2.
Am J Physiol Renal Physiol ; 315(4): F824-F833, 2018 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-29167170

RESUMEN

Accumulation of uremic toxins, which exert deleterious effects in chronic kidney disease, is influenced by the intestinal environment; the microbiota contributes to the production of representative uremic toxins, including p-cresyl sulfate and indoxyl sulfate. Canagliflozin is a sodium-glucose cotransporter (SGLT) 2 inhibitor, and it also exerts a modest inhibitory effect on SGLT1. The inhibition of intestinal SGLT1 can influence the gastrointestinal environment. We examined the effect of canagliflozin on the accumulation of uremic toxins in chronic kidney disease using adenine-induced renal failure mice. Two-week canagliflozin (10 mg/kg po) treatment did not influence the impaired renal function; however, it significantly reduced the plasma levels of p-cresyl sulfate and indoxyl sulfate in renal failure mice (a 75% and 26% reduction, respectively, compared with the vehicle group). Additionally, canagliflozin significantly increased cecal short-chain fatty acids in the mice, suggesting the promotion of bacterial carbohydrate fermentation in the intestine. Analysis of the cecal microbiota showed that canagliflozin significantly altered microbiota composition in the renal failure mice. These results indicate that canagliflozin exerts intestinal effects that reduce the accumulation of uremic toxins including p-cresyl sulfate. Reduction of accumulated uremic toxins by canagliflozin could provide a potential therapeutic option in chronic kidney disease.


Asunto(s)
Canagliflozina/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Insuficiencia Renal Crónica/tratamiento farmacológico , Toxinas Biológicas/sangre , Animales , Modelos Animales de Enfermedad , Tracto Gastrointestinal/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Insuficiencia Renal Crónica/sangre , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Toxinas Biológicas/farmacología , Uremia/sangre , Uremia/tratamiento farmacológico
3.
Kidney Int ; 92(3): 634-645, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28396122

RESUMEN

Gut microbiota is involved in the metabolism of uremic solutes. However, the precise influence of microbiota to the retention of uremic solutes in CKD is obscure. To clarify this, we compared adenine-induced renal failure and control mice under germ-free or specific pathogen-free (SPF) conditions, examining the metabolite profiles of plasma, feces, and urine using a capillary electrophoresis time-of-flight mass spectrometry-based approach. Mice with renal failure under germ-free conditions demonstrated significant changes in plasma metabolites. Among 183 detected solutes, plasma levels of 11 solutes, including major uremic toxins, were significantly lower in germ-free mice than in SPF mice with renal failure. These 11 solutes were considered microbiota-derived uremic solutes and included indoxyl sulfate, p-cresyl sulfate, phenyl sulfate, cholate, hippurate, dimethylglycine, γ-guanidinobutyrate, glutarate, 2-hydroxypentanoate, trimethylamine N-oxide, and phenaceturate. Metabolome profiling showed that these solutes were classified into three groups depending on their origins: completely derived from microbiota (indoxyl sulfate, p-cresyl sulfate), derived from both host and microbiota (dimethylglycine), and derived from both microbiota and dietary components (trimethylamine N-oxide). Additionally, germ-free renal failure conditions resulted in the disappearance of colonic short-chain fatty acids, decreased utilization of intestinal amino acids, and more severe renal damage compared with SPF mice with renal failure. Microbiota-derived short-chain fatty acids and efficient amino acid utilization may have a renoprotective effect, and loss of these factors may exacerbate renal damage in germ-free mice with renal failure. Thus, microbiota contributes substantially to the production of harmful uremic solutes, but conversely, growth without microbiota has harmful effects on CKD progression.


Asunto(s)
Lesión Renal Aguda/metabolismo , Microbioma Gastrointestinal/fisiología , Metaboloma , Insuficiencia Renal Crónica/metabolismo , Toxinas Biológicas/sangre , Uremia/metabolismo , Lesión Renal Aguda/sangre , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/orina , Adenina/toxicidad , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Electroforesis Capilar , Ácidos Grasos Volátiles/análisis , Ácidos Grasos Volátiles/metabolismo , Humanos , Riñón/patología , Espectrometría de Masas , Metabolómica/métodos , Ratones , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/orina , Organismos Libres de Patógenos Específicos , Toxinas Biológicas/orina , Uremia/sangre , Uremia/orina
4.
Nat Commun ; 10(1): 1835, 2019 04 23.
Artículo en Inglés | MEDLINE | ID: mdl-31015435

RESUMEN

Diabetic kidney disease is a major cause of renal failure that urgently necessitates a breakthrough in disease management. Here we show using untargeted metabolomics that levels of phenyl sulfate, a gut microbiota-derived metabolite, increase with the progression of diabetes in rats overexpressing human uremic toxin transporter SLCO4C1 in the kidney, and are decreased in rats with limited proteinuria. In experimental models of diabetes, phenyl sulfate administration induces albuminuria and podocyte damage. In a diabetic patient cohort, phenyl sulfate levels significantly correlate with basal and predicted 2-year progression of albuminuria in patients with microalbuminuria. Inhibition of tyrosine phenol-lyase, a bacterial enzyme responsible for the synthesis of phenol from dietary tyrosine before it is metabolized into phenyl sulfate in the liver, reduces albuminuria in diabetic mice. Together, our results suggest that phenyl sulfate contributes to albuminuria and could be used as a disease marker and future therapeutic target in diabetic kidney disease.


Asunto(s)
Albuminuria/etiología , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/sangre , Microbioma Gastrointestinal/fisiología , Ésteres del Ácido Sulfúrico/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Albuminuria/sangre , Albuminuria/tratamiento farmacológico , Albuminuria/patología , Animales , Animales Modificados Genéticamente , Estudios de Cohortes , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/orina , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 2/sangre , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/patología , Perros , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Células de Riñón Canino Madin Darby , Masculino , Metabolómica/métodos , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Transportadores de Anión Orgánico/genética , Podocitos/metabolismo , Podocitos/patología , Ratas , Estreptozocina/toxicidad , Ésteres del Ácido Sulfúrico/sangre , Tirosina Fenol-Liasa/antagonistas & inhibidores , Tirosina Fenol-Liasa/metabolismo , Adulto Joven
5.
Artículo en Inglés | MEDLINE | ID: mdl-29024911

RESUMEN

Column choice is crucial to the development of liquid chromatography/tandem mass spectrometry (LC-MS/MS) methods because analyte selectivity is dependent on the nature of the stationary phase. Recently, mixed-mode chromatography, which employs a combination of two or more stationary phases and solvent systems, has emerged as an alternative to multiple, complementary, single-column systems. This report describes the development and validation of a novel analytical method based on LC-MS/MS employing a reversed-phase/cation-exchange/anion-exchange tri-modal column (Scherzo SS-C18; Imtakt) for the simultaneous quantification of various uremic toxins (UTx), including creatinine, 1-methyladenosine, trimethylamine-N-oxide, indoxyl sulfate, p-cresyl sulfate, phenyl sulfate and 4-ethylphenyl sulfate. Stable isotope-labeled compounds were prepared as internal standards (ISs) for each analyte. Mobile phase optimization and appropriate gradient conditions resulted in satisfactory retention and peak resolution that could not have been attained with a single stationary phase LC system. The essential validation parameters, including intra- and inter-assay precision and accuracy, were adequate. The validated method was applied to measure serum levels of the aforementioned compounds in 19 patients with chronic kidney disease. This is the first report detailing the simultaneous quantification of these analytes using stable isotopes as ISs. Our results suggest that Scherzo SS-C18 columns will be considered breakthrough tools in the development of analytical methods for compounds that are difficult to quantify simultaneously in traditional LC systems.


Asunto(s)
Cromatografía por Intercambio Iónico/métodos , Cromatografía de Fase Inversa/métodos , Espectrometría de Masas en Tándem/métodos , Toxinas Biológicas/sangre , Humanos , Modelos Lineales , Insuficiencia Renal Crónica/sangre , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
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