Blocking TGF-β signaling pathway preserves mitochondrial proteostasis and reduces early activation of PDGFRβ+ pericytes in aristolochic acid induced acute kidney injury in wistar male rats

The platelet-derived growth factor receptor β (PDGFRβ)+ perivascular cell activation becomes increasingly recognized as a main source of scar-associated kidney myofibroblasts and recently emerged as a new cellular therapeutic target.In this regard, we first confirmed the presence of PDGFRβ+ perivascular cells in a human case of end-stage aristolochic acid nephropathy (AAN) and thereafter we focused on the early fibrosis events of transforming growth factor β (TGFβ) inhibition in a rat model of AAN.Neutralizing anti-TGFβ antibody (1D11) and its control isotype (13C4) were administered (5 mg/kg, i.p.) at Days -1, 0, 2 and 4; AA (15 mg/kg, sc) was injected daily.At Day 5, 1D11 significantly suppressed p-Smad2/3 signaling pathway improving renal function impairment, reduced the score of acute tubular necrosis, peritubular capillaritis, interstitial inflammation and neoangiogenesis. 1D11 markedly decreased interstitial edema, disruption of tubular basement membrane loss of brush border, cytoplasmic edema and organelle ultrastructure alterations (mitochondrial disruption and endoplasmic reticulum edema) in proximal tubular epithelial cells. Moreover, 1D11 significantly inhibited p-PERK activation and attenuated dysregulation of unfolded protein response (UPR) pathways, endoplasmic reticulum and mitochondrial proteostasis in vivo and in vitro.The early inhibition of p-Smad2/3 signaling pathway improved acute renal function impairment, partially prevented epithelial-endothelial axis activation by maintaining PTEC proteostasis and reduced early PDGFRβ+ pericytes-derived myofibroblasts accumulation

The association of birth order with later body mass index and blood pressure: a comparison between prospective cohort studies from the United Kingdom and Brazil

Published online 29 October 2013Previous studies have found greater adiposity and cardiovascular risk in first born children. The causality of this association is not clear. Examining the association in diverse populations may lead to improved insight.We examine the association between birth order and body mass index (BMI), systolic and diastolic blood pressure (SBP/DBP) in the 2004 Pelotas cohort from southern Brazil and the Avon Longitudinal Study of Parents and Children (ALSPAC) from Bristol, south-west England, restricting analysis to families with two children in order to remove confounding by family size.No consistent differences in BMI, SBP or DBP were observed comparing first and second born children. Within the Pelotas 2004 cohort, first born females were thinner, with lower SBP and DBP; for example, mean difference in SBP comparing first with second born was -0.979 (95% confidence interval -2.901 to 0.943). In ALSPAC, first born females had higher BMI, SBP and DBP. In both cohorts, associations tended to be in the opposite direction in males, although no statistical evidence for gender interactions was found.The findings do not support an association between birth order and BMI or blood pressure. Differences to previous studies may be explained by differences in populations and/or confounding by family size in previous studies.L D Howe, P C Hallal, A Matijasevich, J C Wells, I S Santos, A J D Barros, D A Lawlor, C G Victora and G D Smit

Impact of maternal and paternal preconception health on birth outcomes using prospective couples’ data in Add Health

PURPOSE: Retrospective studies of preconception health have demonstrated that parents’ health conditions and behaviors can impact a newborn’s birth outcomes and, subsequently, future health status. This study sought to examine the impact of preconception health, measured prospectively, among both mothers and fathers, on two important birth outcomes: birthweight and gestational age. METHODS: Data came from Add Health (the National Longitudinal Study of Adolescent Health), which included interviews with original participants and a subsample of their partners in 2001–02. In 2008, the original respondents again completed an interview for Add Health. For 372 eligible infants born to these couples, birth outcomes (measured in 2008) were regressed on preconception health conditions and behaviors among non-pregnant heterosexual partners (measured in 2001–02). RESULTS: Mean birthweight was 3399 grams, and mean gestational age was 39 weeks. Birthweight was higher for infants born to mothers with diabetes or high blood pressure, and for mothers who drank alcohol at least once per month, and lower for infants born to fathers with diabetes (p < .05). Infant gestational age was marginally lower for infants born to mothers with higher levels of depression (p < .10), and lower for infants born to fathers with diabetes and with higher levels of fast food consumption (p < .05). CONCLUSIONS: Both maternal and paternal preconception health conditions and behaviors influenced infant birth outcomes. Interventions to promote preconception health should focus on prevention of diabetes and high blood pressure, as well as minimizing consumption of alcohol and fast food