Background Nephron number is a major determinant of long-term renal function and cardiovascular risk. Observational studies suggest that maternal nutritional and metabolic factors during gestation contribute to the high variability of nephron endowment. However, the underlying molecular mechanisms have been unclear. Methods We used mouse models, including DNA methyltransferase (Dnmt1, Dnmt3a, and Dnmt3b) knockout mice, optical projection tomography, three-dimensional reconstructions of the nephrogenic niche, and transcriptome and DNA methylation analysis to characterize the role of DNA methylation for kidney development. Results We demonstrate that DNA hypomethylation is a key feature of nutritional kidney growth restriction in vitro and in vivo, and that DNA methyltransferases Dnmt1 and Dnmt3a are highly enriched in the nephrogenic zone of the developing kidneys. Deletion of Dnmt1 in nephron progenitor cells (in contrast to deletion of Dnmt3a or Dnm3b) mimics nutritional models of kidney growth restriction and results in a substantial reduction of nephron number as well as renal hypoplasia at birth. In Dnmt1-deficient mice, optical projection tomography and three-dimensional reconstructions uncovered a significant reduction of stem cell niches and progenitor cells. RNA sequencing analysis revealed that global DNA hypomethylation interferes in the progenitor cell regulatory network, leading to downregulation of genes crucial for initiation of nephrogenesis, Wt1 and its target Wnt4. Derepression of germline genes, protocadherins, Rhox genes, and endogenous retroviral elements resulted in the upregulation of IFN targets and inhibitors of cell cycle progression. Conclusions These findings establish DNA methylation as a key regulatory event of prenatal renal programming, which possibly represents a fundamental link between maternal nutritional factors during gestation and reduced nephron number.

Background: People forced to leave their homes, such as refugees and internally displaced persons, are exposed to various stressors during their forced displacement, putting them at risk for mental disorders. Objective: To summarize evidence on the efficacy of psychosocial interventions aiming to promote mental health and/or to prevent mental symptoms by fostering transdiagnostic skills in forcibly displaced persons of all ages. Method: Four databases and reference lists were searched for randomized controlled trials on interventions in this population on 11 March 2022. Thirty-six studies were eligible, 32 studies (comprising 5299 participants) were included in random-effects multilevel meta-analyses examining the effects of interventions on mental symptoms and positive mental health (e.g. wellbeing) as well as moderators to account for heterogeneity. OSF Preregistration-ID: 10.17605/OSF.IO/XPMU3 Results: Our search resulted in 32 eligible studies, with 10 reporting on children/adolescents and 27 on adult populations. There was no evidence for favourable intervention effects in children/adolescents, with 44.4% of the effect sizes pointing to potentially negative effects yet remaining non-significant. For adult populations, our meta-analyses showed a close-to-significant favourable effect for mental symptoms, M (SMD) = 0.33, 95% CI [–0.03, 0.69], which was significant when analyses were limited to high-quality studies and larger for clinical compared to non-clinical populations. No effects emerged for positive mental health. Heterogeneity was considerable and could not be explained by various moderators (e.g. type of control, duration, setting, theoretical basis). Certainty of evidence was very low across all outcomes limiting the generalizability of our findings. Conclusion: The present review provides at most weak evidence for an effect favouring transdiagnostic psychosocial interventions over control conditions for adult populations but not for children and adolescents. Future research should combine the imperative of humanitarian aid in face of major crises with studying the diverse needs of forcibly displaced persons to improve and tailor future interventions.

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A growing body of evidence suggests that low nephron numbers at birth can increase the risk of chronic kidney disease or hypertension later in life. Environmental stressors, such as maternal malnutrition, medication and smoking, can influence renal size at birth. Using metanephric organ cultures to model single-variable environmental conditions, models of maternal disease were evaluated for patterns of developmental impairment. While hyperthermia had limited effects on renal development, fetal iron deficiency was associated with severe impairment of renal growth and nephrogenesis with an all-proximal phenotype. Culturing kidney explants under high glucose conditions led to cellular and transcriptomic changes resembling human diabetic nephropathy. Short-term high glucose culture conditions were sufficient for long-term alterations in DNA methylation-associated epigenetic memory. Finally, the role of epigenetic modifiers in renal development was tested using a small compound library. Among the selected epigenetic inhibitors, various compounds elicited an effect on renal growth, such as HDAC (entinostat, TH39), histone demethylase (deferasirox, deferoxamine) and histone methyltransferase (cyproheptadine) inhibitors. Thus, metanephric organ cultures provide a valuable system for studying metabolic conditions and a tool for screening for epigenetic modifiers in renal development.