Renal Programming by Transient Postnatal Overfeeding: The Role of Senescence Pathways

Abstract

Background: Early 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 Methods: Reduced 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. Results: Early 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. Conclusion: Early 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.

Cellular senescence: the good, the bad and the unknown

“…Podocyte senescence induces glomerulosclerosis in the ageing kidney via AMPK–mTOR signalling 199 , whereas DKD or overfeeding can induce renal cellular senescence by decreasing sirtuin 1 expression 200 . In patients with DKD, the circulating senescence marker activin A is elevated 161 and p16 is upregulated in tubular epithelial cells 201 .…”

Effect of Protein Intake Early in Life on Kidney Volume and Blood Pressure at 11 Years of Age

“…Low nephron endowment is linked to worse cardiovascular and kidney outcomes, as demonstrated in animal and epidemiologic studies [ 3 ]. On the other hand, glomerular hypertrophy due to overload has also been shown to have a deleterious effect on glomerular sclerosis and apoptosis in the long run [ 21 ]. Higher protein ingestion is one of the factors that could contribute to that overload.…”

“…An interesting study conducted in rats demonstrated that early overfeeding (protein and calories) leads to a higher body mass index, kidney weight, glomeruli number (nephrogenesis continues after birth in rats), and blood pressure in adult rats, but also a higher number and larger distribution of senescent cells in the kidneys at weaning [ 21 ]. Because, in humans, nephrogenesis ends at 36 weeks of gestational age, the effect of higher protein ingestion early in life on kidney volume and blood pressure at 11 years of age cannot be explained by an increase in the glomeruli number.…”

Exploring the Critical Components and Therapeutic Mechanisms of Perilla frutescens L. in the Treatment of Chronic Kidney Disease via Network Pharmacology

“…IL6 is regarded as a proinflammatory cytokine, which plays a key role in the immune response and inflammation. Both p53 and IL6 are involved in the development of CKD, and can aggravate renal injury by inducing apoptosis, promoting inflammation, accelerating cell senescence and other ways (Amdur et al, 2016;Juvet et al, 2020;. Therefore, we also detected the phosphorylation level of p53 and the expression of IL6.…”