Abstract
BackgroundEarly nutrition influences the risk of chronic kidney diseases (CKDs) development in adulthood. Mechanisms underlying the early programming of altered renal function remain incompletely understood. This study aims at characterizing the role of cell senescence pathways in early programming of CKD after transient postnatal overfeeding.Materials and MethodsReduced litters of 3 mice pups and standard litters of 9 mice pups were obtained to induce overfed animals during lactation and control animals, respectively. Animals were sacrificed at 24 days (weaning) or at 7 months of life (adulthood). Body weight, blood pressure, kidney weight, and glomerular count were assessed in both groups. Senescence pathways were investigated using β-Galactosidase staining and Western blotting of P16, P21, P53, P-Rb/Rb, and Sirtuin 1 (Sirt1) proteins.ResultsEarly overfed animals had a higher body weight, a higher blood pressure at adulthood, and a higher glomerular number endowment compared to the control group. A higher β-Galactosidase activity, a significant increase in P53 protein expression (p = 0.0045) and a significant decrease in P-Rb/Rb ratio (p = 0.02), were observed at weaning in animals who underwent early postnatal overfeeding. Protein expression of Sirt1, a protective factor against accelerated stress-induced senescence, was significantly decreased (p = 0.03) at weaning in early overfed animals.ConclusionEarly postnatal overfeeding by litter size reduction is associated with increased expression of factors involved in cellular senescence pathways, and decreased expression of Sirt 1 in the mouse kidney at weaning. These alterations may contribute to CKD programming after early postnatal overfeeding.
Highlights
An upward trend in the prevalence of non-communicable diseases (NCDs) with developmental origins, including chronic kidney disease (CKD) and arterial hypertension is observed worldwide (Hanson et al, 2011; Barouki et al, 2012)
At 6 months of age, systolic, diastolic and mean arterial Blood Pressure (BP) were significantly higher in animals who underwent early postnatal overfeeding compared to the control group
The higher number of senescent cells in the kidney after early postnatal overfeeding demonstrated by a higher β-Galactosidase staining, was confirmed by quantification of protein expression of factors involved in cellular senescence pathways at weaning (Figure 5)
Summary
An upward trend in the prevalence of non-communicable diseases (NCDs) with developmental origins, including chronic kidney disease (CKD) and arterial hypertension is observed worldwide (Hanson et al, 2011; Barouki et al, 2012). In a New York clinical-pathologic study, the proportion of all renal biopsies that displayed obesity-related kidney damage, in particular focal segmental glomerulosclerosis (FSGS), increased 10 folds from 1986 to 2000 (Kambham et al, 2001) In both human and animal studies, early postnatal overfeeding and excessive weight gain have been associated with adverse outcomes in the vascular and renal systems in adulthood (Boubred et al, 2007, 2009; Alcazar et al, 2012; Yim et al, 2012, 2013, 2014; Adair et al, 2013). This study aims at characterizing the role of cell senescence pathways in early programming of CKD after transient postnatal overfeeding
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