Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Filtrar
1.
Proc Natl Acad Sci U S A ; 113(43): 12298-12303, 2016 10 25.
Artículo en Inglés | MEDLINE | ID: mdl-27791019

RESUMEN

Melanocortin-4 receptor (Mc4r)-expressing neurons in the autonomic nervous system, particularly in the paraventricular nucleus of the hypothalamus (PVH), play an essential role in blood pressure (BP) control. Mc4r-deficient (Mc4rKO) mice are severely obese but lack obesity-related hypertension; they also show a reduced pressor response to salt loading. We have previously reported that lean juvenile offspring born to diet-induced obese rats (OffOb) exhibit sympathetic-mediated hypertension, and we proposed a role for postnatally raised leptin in its etiology. Here, we test the hypothesis that neonatal hyperleptinemia due to maternal obesity induces persistent changes in the central melanocortin system, thereby contributing to offspring hypertension. Working on the OffOb paradigm in both sexes and using transgenic technology to restore Mc4r in the PVH of Mc4rKO (Mc4rPVH) mice, we have now shown that these mice develop higher BP than Mc4rKO or WT mice. We have also found that experimental hyperleptinemia induced in the neonatal period in Mc4rPVH and WT mice, but not in the Mc4rKO mice, leads to heightened BP and severe renal dysfunction. Thus, Mc4r in the PVH appears to be required for early-life programming of hypertension arising from either maternal obesity or neonatal hyperleptinemia. Early-life exposure of the PVH to maternal obesity through postnatal elevation of leptin may have long-term consequences for cardiovascular health.


Asunto(s)
Hipertensión/genética , Leptina/metabolismo , Obesidad/genética , Efectos Tardíos de la Exposición Prenatal/genética , Receptor de Melanocortina Tipo 4/genética , Animales , Presión Sanguínea/genética , Dieta/efectos adversos , Modelos Animales de Enfermedad , Femenino , Humanos , Hipertensión/complicaciones , Hipertensión/fisiopatología , Leptina/genética , Masculino , Relaciones Materno-Fetales/fisiología , Ratones Noqueados , Neuronas/metabolismo , Neuronas/patología , Obesidad/complicaciones , Obesidad/fisiopatología , Núcleo Hipotalámico Paraventricular/metabolismo , Núcleo Hipotalámico Paraventricular/patología , Embarazo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Sistema Nervioso Simpático/metabolismo , Sistema Nervioso Simpático/patología
2.
BMC Nephrol ; 18(1): 153, 2017 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-28482823

RESUMEN

BACKGROUND: The pathological condition of chronic kidney disease may not be adequately recapitulated in immunocompromised mice due to the lack of T-cells, which are important for the development of hypertension and renal injury. We studied the role of the immune system in relation to salt-sensitive hypertension and renal injury in mice with subtotal nephrectomy (SNX). METHODS: Wild-type immunocompetent (WT) and Foxn1nu/nu athymic immunodeficient (AT) CD-1 mice underwent SNX to induce renal injury after which they received standard chow or a high salt diet (HSD). Four weeks after SNX blood pressure and kidney function parameters were measured. RESULTS: HSD increased albumin excretion independent of immune status. Systolic blood pressure increased only in WT mice on HSD, not in AT mice. Uremia and morphological damage after SNX were not affected by either HSD or immune status. CONCLUSIONS: For the development of hypertension after SNX in CD-1 mice mature T-cells and a high salt diet are required. SNX induced albuminuria was independent of the presence of T-cells.


Asunto(s)
Lesión Renal Aguda/inmunología , Hipertensión Renal/inmunología , Hipertensión Renal/patología , Nefrectomía/efectos adversos , Cloruro de Sodio Dietético/efectos adversos , Linfocitos T/inmunología , Lesión Renal Aguda/etiología , Lesión Renal Aguda/patología , Animales , Hipertensión Renal/etiología , Masculino , Ratones , Ratones Desnudos , Linfocitos T/patología
3.
Nitric Oxide ; 49: 56-66, 2015 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-26192363

RESUMEN

Hydrogen sulfide (H2S), carbon monoxide (CO) and nitric oxide (NO) share signaling and vasorelaxant properties and are involved in proliferation and apoptosis. Inhibiting NO production or availability induces hypertension and proteinuria, which is prevented by concomitant blockade of the H2S producing enzyme cystathionine γ-lyase (CSE) by d,l-propargylglycine (PAG). We hypothesized that blocking H2S production ameliorates Angiotensin II (AngII)-induced hypertension and renal injury in a rodent model. Effects of concomitant administration of PAG or saline were therefore studied in healthy (CON) and AngII hypertensive rats. In CON rats, PAG did not affect systolic blood pressure (SBP), but slightly increased proteinuria. In AngII rats PAG reduced SBP, proteinuria and plasma creatinine (180 ± 12 vs. 211 ± 19 mmHg; 66 ± 35 vs. 346 ± 92 mg/24 h; 24 ± 6 vs. 47 ± 15 µmol/L, respectively; p < 0.01). Unexpectedly, kidney to body weight ratio was increased in all groups by PAG (p < 0.05). Renal injury induced by AngII was reduced by PAG (p < 0.001). HO-1 gene expression was increased by PAG alone (p < 0.05). PAG increased inner cortical tubular cell proliferation after 1 week and decreased outer cortical tubular nucleus number/field after 4 weeks. In vitro proximal tubular cell size increased after exposure to PAG. In summary, blocking H2S production with PAG reduced SBP and renal injury in AngII infused rats. Independent of the cardiovascular and renal effects, PAG increased HO-1 gene expression and kidney weight. PAG alone increased tubular cell size and proliferation in-vivo and in-vitro. Our results are indicative of a complex interplay of gasotransmitter signaling/action of mutually compensatory nature in the kidney.


Asunto(s)
Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/metabolismo , Alquinos/farmacología , Angiotensina II/efectos adversos , Presión Sanguínea/efectos de los fármacos , Glicina/análogos & derivados , Sulfuro de Hidrógeno/metabolismo , Alquinos/administración & dosificación , Animales , Proliferación Celular , Glicina/administración & dosificación , Glicina/farmacología , Hemo-Oxigenasa 1/metabolismo , Riñón/efectos de los fármacos , Riñón/patología , Masculino , Óxido Nítrico , Tamaño de los Órganos , Ratas , Ratas Sprague-Dawley
4.
J Hypertens ; 38(3): 489-503, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31652182

RESUMEN

OBJECTIVE: Left ventricular (LV) hypertrophy is the most common cardiac alteration in patients with chronic kidney disease (CKD). Normalization of hypertension in CKD patients receiving a healthy kidney allograft often reverses LV hypertrophy, but effects on LV fibrosis remain unclear. To study causal interactions between graft and environment on LV hypertrophy, fibrosis and inflammation, we applied cross-kidney transplantation METHODS:: Orthotopic transplantation was performed after inducing CKD in rats by two-third bilateral ablation of kidney mass: Healthy kidney (K) donor to healthy heart (H) recipient (healthy-K→healthy-H); CKD-K→healthy-H; healthy-K→CKD-H; CKD-K→CKD-H; N= 6 per group. RESULTS: At week 6 after transplantation, mean arterial pressure (MAP) and LV mass index (LVMI) increased in CKD-K versus healthy-K irrespective of recipient. Contrarily, LV fibrosis was more severe in CKD-H versus healthy-H recipients irrespective of graft. Indeed, MAP and plasma creatinine correlated with LVMI but not with LV fibrosis. Increased LVMI in CKD-K→CKD-H not accompanied by cardiomyocyte cross-sectional area gain is consistent with eccentric remodelling. Cardiac RNA sequencing found a strong transcriptional response associated with LV fibrosis but only sparse changes associated with LV hypertrophy. This response was, among others, characterized by changes in extracellular matrix (ECM) and inflammatory gene expression. CONCLUSION: LVMI reversed and MAP and renal function were normalized early after transplantation of a healthy kidney. However, LV fibrosis persisted, dissociating LV hypertrophy from LV fibrosis within 6 weeks. Elucidating cardiac ECM dynamics in CKD patients, although challenging, appears promising.


Asunto(s)
Ventrículos Cardíacos , Hipertrofia Ventricular Izquierda , Trasplante de Riñón , Insuficiencia Renal Crónica/complicaciones , Animales , Modelos Animales de Enfermedad , Fibrosis/complicaciones , Fibrosis/patología , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/fisiopatología , Hipertrofia Ventricular Izquierda/complicaciones , Hipertrofia Ventricular Izquierda/patología , Hipertrofia Ventricular Izquierda/fisiopatología , Ratas
5.
Dis Model Mech ; 11(7)2018 07 17.
Artículo en Inglés | MEDLINE | ID: mdl-30038062

RESUMEN

Kidney transplantation (Tx) is considered the only definite treatment for end-stage kidney disease (ESKD) patients. The increasing prevalence of ESKD has necessitated the introduction of transplantation with kidneys from suboptimal donors. There is, however, still a lack of fundamental and longitudinal research on suboptimal kidney transplants. Specifically, there is a demand for accurate pre-Tx predictors of donor kidney function and injury to predict post-Tx outcome. In the present study, we combine rat models of chronic kidney disease (CKD) and renal Tx to dissect the effects of healthy and CKD renal grafts on healthy and CKD recipients. We show that renal function at 6 weeks post-Tx is exclusively determined by donor graft quality. Using cell tracking within enhanced green fluorescent protein-positive (eGFP+) recipients, we furthermore show that most inflammatory cells within the donor kidney originate from the donor. Oxidative and vascular extra-renal damage were, in contrast, determined by the recipient. Post- versus pre-Tx evaluation of grafts showed an increase in glomerular and peritubular capillary rarefaction in healthy but not CKD grafts within a CKD environment. Proliferation of glomerular endothelium was similar in all groups, and influx of eGFP+ recipient-derived cells occurred irrespective of graft or recipient status. Glomerular and peritubular capillary rarefaction, severity of inflammation and macrophage subtype data post-Tx were, however, determined by more complicated effects, warranting further study. Our experimental model could help to further distinguish graft from recipient environment effects, leading to new strategies to improve graft survival of suboptimal Tx kidneys.This article has an associated First Person interview with the first author of the paper.


Asunto(s)
Células Endoteliales/patología , Inflamación/patología , Trasplante de Riñón , Animales , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Proliferación Celular , Células Endoteliales/metabolismo , Proteínas Fluorescentes Verdes/metabolismo , Inmunohistoquímica , Riñón/patología , Riñón/fisiopatología , Pruebas de Función Renal , Macrófagos/patología , Masculino , Óxido Nítrico Sintasa de Tipo II/metabolismo , Estrés Oxidativo , Ratas Endogámicas Lew , Receptores de Superficie Celular/metabolismo
6.
J Hypertens ; 35(12): 2537-2547, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28704264

RESUMEN

BACKGROUND: Material obesity in rodents is associated with neonatal hyperleptinemia and hypertension of sympathetic origin in adult offspring. Previously, we reported that experimentally induced hyperleptinemia in rat pups results in adulthood hypertension. Here, we addressed the hypothesis that experimental neonatal hyperleptinemia, through renal nerve activation, adversely affects adult renal function. METHOD: Sprague-Dawley male and female pups were treated with neonatal leptin (3 mg/kg, intraperitoneal) or neonatal saline, twice daily from postnatal day 9-14. Juvenile (1 month) neonatal leptin and neonatal saline rats were subjected to either bilateral renal denervation, unilateral renal denervation or Sham surgery. Arterial pressure was telemetrically monitored. RESULTS: Juvenile neonatal leptin rats with intact renal nerves demonstrated increased mean arterial pressure (MAP) accompanied by local renin-angiotensin system overactivity and reduced glomerular filtration rate. Bilateral renal denervation in rats protected against neonatal leptin-induced MAP, renal renin-angiotensin system and impaired glomerular filtration rate. A two-fold increase in sympathetically mediated tubulointerstitial damage in young adult (2 months) neonatal leptin females, was suppressed by unilateral renal denervation, independent of MAP. Neonatal leptin rats also demonstrated increases in urinary protein, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1. Raised blood pressure was associated with increased salt sensitivity and with sustained renal dysfunction in adulthood. CONCLUSION: We propose that neonatal hyperleptinemia programmes long-term renal structural and functional damage, through renal sympathetic nerve activation.


Asunto(s)
Presión Sanguínea/fisiología , Desnervación , Hipertensión/cirugía , Enfermedades Renales/cirugía , Riñón/inervación , Leptina/sangre , Animales , Modelos Animales de Enfermedad , Femenino , Hipertensión/sangre , Hipertensión/fisiopatología , Riñón/fisiopatología , Enfermedades Renales/sangre , Enfermedades Renales/fisiopatología , Lipocalina 2/sangre , Masculino , Ratas , Ratas Sprague-Dawley , Sistema Nervioso Simpático/fisiopatología
7.
Circ Heart Fail ; 9(4): e002760, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27056881

RESUMEN

BACKGROUND: The combination of cardiac and renal disease driven by metabolic risk factors, referred to as cardiorenal metabolic syndrome (CRMS), is increasingly recognized as a critical pathological entity. The contribution of (micro)vascular injury to CRMS is considered to be substantial. However, mechanistic studies are hampered by lack of in vivo models that mimic the natural onset of the disease. Here, we evaluated the coronary and renal microvasculature during CRMS development in obese diabetic Zucker fatty/Spontaneously hypertensive heart failure F1 hybrid (ZSF1) rats. METHODS AND RESULTS: Echocardiographic, urine, and blood evaluations were conducted in 3 groups (Wistar-Kyoto, lean ZSF1, and obese ZSF1) at 20 and 25 weeks of age. Immunohistological evaluation of renal and cardiac tissues was conducted at both time points. At 20 and 25 weeks, obese ZSF1 rats showed higher body weight, significant left ventricular hypertrophy, and impaired diastolic function compared with all other groups. Indices of systolic function did not differ between groups. Obese ZSF1 rats developed hyperproliferative vascular foci in the subendocardium, which lacked microvascular organization and were predilection sites of inflammation and fibrosis. In the kidney, obese ZSF1 animals showed regression of the peritubular and glomerular microvasculature, accompanied by tubulointerstitial damage, glomerulosclerosis, and proteinuria. CONCLUSIONS: The obese ZSF1 rat strain is a suitable in vivo model for CRMS, sharing characteristics with the human syndrome during the earliest onset of disease. In these rats, CRMS induces microvascular fibrotic responses in heart and kidneys, associated with functional impairment of both organs.


Asunto(s)
Síndrome Cardiorrenal/etiología , Vasos Coronarios , Células Endoteliales , Insuficiencia Cardíaca/etiología , Riñón/irrigación sanguínea , Síndrome Metabólico/complicaciones , Microvasos , Volumen Sistólico , Función Ventricular Izquierda , Animales , Síndrome Cardiorrenal/diagnóstico , Síndrome Cardiorrenal/metabolismo , Síndrome Cardiorrenal/fisiopatología , Proliferación Celular , Vasos Coronarios/metabolismo , Vasos Coronarios/patología , Vasos Coronarios/fisiopatología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Células Endoteliales/metabolismo , Células Endoteliales/patología , Fibrosis , Glomerulonefritis/etiología , Glomerulonefritis/fisiopatología , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/fisiopatología , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/fisiopatología , Masculino , Síndrome Metabólico/diagnóstico , Síndrome Metabólico/metabolismo , Síndrome Metabólico/fisiopatología , Microvasos/metabolismo , Microvasos/patología , Microvasos/fisiopatología , Proteinuria/etiología , Proteinuria/fisiopatología , Ratas Endogámicas WKY , Ratas Zucker , Factores de Tiempo , Remodelación Vascular , Remodelación Ventricular
8.
Stem Cell Res Ther ; 6: 63, 2015 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-25889756

RESUMEN

INTRODUCTION: Healthy bone marrow cell (BMC) infusion improves renal function and limits renal injury in a model of chronic kidney disease (CKD) in rats. However, BMCs derived from rats with CKD fail to retain beneficial effects, demonstrating limited therapeutic efficacy. Statins have been reported to improve cellular repair mechanisms. METHODS: We studied whether exposing CKD rat BMCs ex vivo to pravastatin improved their in vivo therapeutic efficacy in CKD and compared this to systemic in vivo treatment. Six weeks after CKD induction, healthy BMCs, healthy pravastatin-pretreated BMCs, CKD BMCs or CKD pravastatin-pretreated BMCs were injected into the renal artery of CKD rats. RESULTS: At 6 weeks after BMC injection renal injury was reduced in pravastatin-pretreated CKD BMC recipients vs. CKD BMC recipients. Effective renal plasma flow was lower and filtration fraction was higher in CKD BMC recipients compared to all groups whereas there was no difference between pravastatin-pretreated CKD BMC and healthy BMC recipients. Mean arterial pressure was higher in CKD BMC recipients compared to all other groups. In contrast, 6 weeks of systemic in vivo pravastatin treatment had no effect. In vitro results showed improved migration, decreased apoptosis and lower excretion of pro-inflammatory Chemokine (C-X-C Motif) Ligand 5 in pravastatin-pretreated CKD BMCs. CONCLUSIONS: Short ex vivo exposure of CKD BMC to pravastatin improves CKD BMC function and their subsequent therapeutic efficacy in a CKD setting, whereas systemic statin treatment did not provide renal protection.


Asunto(s)
Células de la Médula Ósea/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Pravastatina/farmacología , Insuficiencia Renal Crónica/patología , Animales , Apoptosis , Presión Sanguínea , Peso Corporal , Células de la Médula Ósea/citología , Células de la Médula Ósea/metabolismo , Trasplante de Médula Ósea , Movimiento Celular , Quimiocina CXCL5/análisis , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Tasa de Filtración Glomerular , Riñón/irrigación sanguínea , Riñón/fisiología , Masculino , Ratas , Ratas Endogámicas Lew , Insuficiencia Renal Crónica/terapia , Insuficiencia Renal Crónica/veterinaria , Donantes de Tejidos , Trasplante Homólogo
9.
Dis Model Mech ; 8(3): 281-93, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25633980

RESUMEN

Cell-based therapy is a promising strategy for treating chronic kidney disease (CKD) and is currently the focus of preclinical studies. We performed a systematic review and meta-analysis to evaluate the efficacy of cell-based therapy in preclinical (animal) studies of CKD, and determined factors affecting cell-based therapy efficacy in order to guide future clinical trials. In total, 71 articles met the inclusion criteria. Standardised mean differences (SMD) and 95% confidence intervals (CI) were calculated for outcome parameters including plasma urea, plasma creatinine, urinary protein, blood pressure, glomerular filtration rate, glomerulosclerosis and interstitial fibrosis. Sub-analysis for each outcome measure was performed for model-related factors (species, gender, model and timing of therapy) and cell-related factors (cell type, condition and origin, administration route and regime of therapy). Overall, meta-analysis showed that cell-based therapy reduced the development and progression of CKD. This was most prominent for urinary protein (SMD, 1.34; 95% CI, 1.00-1.68) and urea (1.09; 0.66-1.51), both P<0.001. Changes in plasma urea were associated with changes in both glomerulosclerosis and interstitial fibrosis. Sub-analysis showed that cell type (bone-marrow-derived progenitors and mesenchymal stromal cells being most effective) and administration route (intravenous or renal artery injection) were significant predictors of therapeutic efficacy. The timing of therapy in relation to clinical manifestation of disease, and cell origin and dose, were not associated with efficacy. Our meta-analysis confirms that cell-based therapies improve impaired renal function and morphology in preclinical models of CKD. Our analyses can be used to optimise experimental interventions and thus support both improved preclinical research and development of cell-based therapeutic interventions in a clinical setting.


Asunto(s)
Tratamiento Basado en Trasplante de Células y Tejidos , Insuficiencia Renal Crónica/terapia , Animales , Presión Sanguínea , Modelos Animales de Enfermedad , Riñón/patología , Riñón/fisiopatología , Evaluación de Resultado en la Atención de Salud , Proteinuria/sangre , Proteinuria/complicaciones , Proteinuria/metabolismo , Sesgo de Publicación , Análisis de Regresión , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/fisiopatología , Urea/sangre
10.
Animals (Basel) ; 4(4): 712-28, 2014 Dec 03.
Artículo en Inglés | MEDLINE | ID: mdl-26479008

RESUMEN

Transfer from the breeding facility to a research facility is a stressful event for laboratory animals. Heat stress has been reported to constitute one of the major concerns during transport of animals. This study measured ambient and body temperature, corticosterone and glucose levels, body weight, behavior and water and food intake before, during and after transfer in Wistar rats. Decreased body weight, water and food intake were observed on the day of transfer in rats. Environmental temperature strongly affected body temperature of rats and needs to be controlled. Male rats need to habituate for at least one week, females for two weeks after transfer.

SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA