ACE2-angiotensin-(1-7)-Mas axis in renal ischaemia/reperfusion injury in rats

AngII (angiotensin II), ACE (angiotensin I-converting enzyme) and the AT(1) receptor (AngII type I receptor) are associated with the inflammatory process and microvascular dysfunction of AKI (acute kidney injury) induced by renal I/R (ischaemia/reperfusion). However, Ang-(1-7) [angiotensin-(1-7)], ACE2 (angiotensin I-converting enzyme 2) and the Mas receptor also play a role in renal disease models. Therefore, in the present study, we have examined the renal profile of Ang-(1-7), ACE2 and the Mas receptor in renal I/R and compared them with that of AngII, ACE and the AT(1) receptor. Male Wistar rats were submitted to left nephrectomy and ischaemia (45 min) followed by reperfusion (2 or 4 h) in the right kidney. At 4 h of reperfusion, renal AngII was increased (P < 0.01) and renal Ang-(1-7) was decreased substantially (P < 0.05), although plasma levels of both angiotensins were unchanged. in addition, renal I/R decreased the renal mRNA expression of renin (P < 0.05), AT(1) receptors (P < 0.001) and ACE2 (P < 0.05). At 2 and 4 h of reperfusion, renal ACE activity was reduced (P < 0.05). On the other hand, renal expression of the Mas receptor was greatly increased at 4 h of reperfusion (P < 0.01), which was confirmed by immunohistochemical and Western blot analysis. in conclusion, increased renal expression of the Mas receptor associated with changes in the RAS (renin-angiotensin-system)-related peptidases support an important role for the ACE2 Ang-(1-7) Mas axis in AKI.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG)Univ Fed Minas Gerais, Inst Biol Sci, Dept Physiol & Biophys, BR-31270901 Belo Horizonte, MG, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Biophys, BR-04044020 São Paulo, SP, BrazilUniv Fed Minas Gerais, Dept Pathol, BR-31270901 Belo Horizonte, MG, BrazilUniv Fed Minas Gerais, Dept Microbiol, BR-31270901 Belo Horizonte, MG, BrazilUniv Fed Minas Gerais, Clin Pathol Unit COLTEC, BR-31270901 Belo Horizonte, MG, BrazilUniv Fed Minas Gerais, Dept Biochem, Inst Biol Sci, BR-31270901 Belo Horizonte, MG, BrazilUniv Fed Minas Gerais, Dept Pediat, Fac Med, BR-31270901 Belo Horizonte, MG, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Biophys, BR-04044020 São Paulo, SP, BrazilCAPES: PRDEX2009CNPq: 8701480/1997-4FAPEMIG: CBS 2044/96Web of Scienc

Understanding the relation between Zika virus infection during pregnancy and adverse fetal, infant and child outcomes: a protocol for a systematic review and individual participant data meta-analysis of longitudinal studies of pregnant women and their infants and children

IntroductionZika virus (ZIKV) infection during pregnancy is a known cause of microcephaly and other congenital and developmental anomalies. In the absence of a ZIKV vaccine or prophylactics, principal investigators (PIs) and international leaders in ZIKV research have formed the ZIKV Individual Participant Data (IPD) Consortium to identify, collect and synthesise IPD from longitudinal studies of pregnant women that measure ZIKV infection during pregnancy and fetal, infant or child outcomes.Methods and analysisWe will identify eligible studies through the ZIKV IPD Consortium membership and a systematic review and invite study PIs to participate in the IPD meta-analysis (IPD-MA). We will use the combined dataset to estimate the relative and absolute risk of congenital Zika syndrome (CZS), including microcephaly and late symptomatic congenital infections; identify and explore sources of heterogeneity in those estimates and develop and validate a risk prediction model to identify the pregnancies at the highest risk of CZS or adverse developmental outcomes. The variable accuracy of diagnostic assays and differences in exposure and outcome definitions means that included studies will have a higher level of systematic variability, a component of measurement error, than an IPD-MA of studies of an established pathogen. We will use expert testimony, existing internal and external diagnostic accuracy validation studies and laboratory external quality assessments to inform the distribution of measurement error in our models. We will apply both Bayesian and frequentist methods to directly account for these and other sources of uncertainty.Ethics and disseminationThe IPD-MA was deemed exempt from ethical review. We will convene a group of patient advocates to evaluate the ethical implications and utility of the risk stratification tool. Findings from these analyses will be shared via national and international conferences and through publication in open access, peer-reviewed journals.Trial registration numberPROSPERO International prospective register of systematic reviews (CRD42017068915).</jats:sec

Una nueva dieta animal basada en la dieta occidental humana es un modelo robusto de obesidad inducida por la dieta: comparación con las dietas ricas en grasas y en la cafetería en términos de alteración metabólica y microbiota intestinal

Background/Objectives:Obesity is a metabolic disorder that predisposes patients to numerous diseases and has become a major global public-health concern. Animal models of diet-induced obesity (DIO) are frequently used to study obesity, but which DIO model most accurately reflects the pathology of human obesity remains unclear. In this study, we designed a diet based on the human Western diet (WD) and compared it with the cafeteria diet (CAF) and high-fat diet (HFD) in order to evaluate which diet most closely mirrors human obesity.Methods:Wistar rats were fed four different diets (WD, CAF, HFD and a low-fat diet) for 18 weeks. Metabolic parameters and gut microbiota changes were then characterized.Results:Rats fed the four different diets exhibited completely different phenotypes, highlighting the importance of diet selection. This study also revealed that WD most effectively induced obesity and obesity-related disorders, and thus proved to be a robust model of human obesity. Moreover, WD-fed rats developed obesity and obesity-related comorbidities independent of major alterations in gut microbiota composition (dysbiosis), whereas CAF-fed rats developed the greatest dysbiosis independent of obesity. We also characterized gut microbiota after feeding on these four different diets and identified five genera that might be involved in the pathogenesis of obesity.Conclusions:These data suggest that diet, and not the obese state, was the major driving force behind gut microbiota changes. Moreover, the marked dysbiosis observed in CAF-fed rats might have resulted from the presence of several additives present in the CAF diet, or even a lack of essential vitamins and minerals. Based on our findings, we recommend the use of the prototypic WD (designed here) in DIO models. Conversely, CAF could be used to investigate the effects of excessive consumption of industrially produced and highly processed foods, which are characteristic of Western society.Antecedentes / Objetivos: La obesidad es un trastorno metabólico que predispone a los pacientes a numerosas enfermedades y se ha convertido en un importante problema de salud pública mundial. Los modelos animales de la obesidad inducida por la dieta (DIO) se utilizan con frecuencia para estudiar la obesidad, pero el modelo DIO que refleja con mayor precisión la patología de la obesidad humana aún no está claro. En este estudio, diseñamos una dieta basada en la dieta occidental humana (WD) y la comparamos con la dieta de cafetería (CAF) y la dieta alta en grasas (HFD) para evaluar qué dieta refleja mejor la obesidad humana. Métodos: Wistar las ratas fueron alimentadas con cuatro dietas diferentes (WD, CAF, HFD y una dieta baja en grasa) durante 18 semanas. Luego se caracterizaron los parámetros metabólicos y los cambios en la microbiota intestinal. Resultados: Las ratas alimentadas con las cuatro dietas diferentes mostraron fenotipos completamente diferentes, destacando la importancia de la selección de la dieta. Este estudio también reveló que la WD inducía con mayor eficacia la obesidad y los trastornos relacionados con la obesidad, y por lo tanto demostró ser un modelo robusto de la obesidad humana. Además, las ratas alimentadas con WD desarrollaron obesidad y comorbilidades relacionadas con la obesidad independientes de alteraciones importantes en la composición de la microbiota intestinal (disbiosis), mientras que las ratas alimentadas con CAF desarrollaron la mayor disbiosis independiente de la obesidad. También caracterizamos la microbiota intestinal después de alimentarnos con estas cuatro dietas diferentes e identificamos cinco géneros que podrían estar involucrados en la patogénesis de la obesidad. Conclusiones: Estos datos sugieren que la dieta, y no el estado obeso, fue la principal fuerza impulsora detrás de los cambios en la microbiota intestinal. Además, la marcada disbiosis observada en ratas alimentadas con CAF podría haber resultado de la presencia de varios aditivos presentes en la dieta CAF, o incluso la falta de vitaminas y minerales esenciales. Sobre la base de nuestros hallazgos, recomendamos el uso del prototipo WD (diseñado aquí) en modelos DIO. A la inversa, CAF podría utilizarse para investigar los efectos del consumo excesivo de alimentos producidos industrialmente y altamente procesados, que son característicos de la sociedad occidental