Maternal protein restriction affects gene expression profiles in the kidney at weaning with implications for the regulation of renal function and lifespan

Nutritionally induced alterations in early growth can influence health and disease in later adult life. We have demonstrated previously that low birthweight resulting from maternal protein restriction during pregnancy followed by accelerated growth in rodents was associated with shortened lifespan, whereas protein restriction and slow growth during lactation increased lifespan. Thus early life events can also have a long lasting impact on longevity. In the present study, we show that long-lived PLP (postnatal low protein) mice were protected from developing albuminuria, whereas short-lived recuperated mice demonstrated an age-dependent increase in albuminuria in old age. Microarray analysis of kidneys from 21-day-old mice revealed that gene expression profiles were differentially affected depending on whether protein restriction was imposed during pregnancy or lactation. The differentially expressed genes were involved in diverse biological functions such as cytoprotective functions, vitamin D synthesis, protein homoeostasis, regulation of antioxidant enzymes and cellular senescence. Significantly, up-regulation of Hmox1 (haem oxygenase 1) in kidneys from PLP mice suggests that tissues of long-lived mice are equipped with a better cytoprotective function. In contrast, up-regulation of Nuak2 (NUAK family, SNF1-like kinase 2) and down-regulation of Lonp2 (Lon peptidase 2), Foxo3a (forkhead box O3a), Sod1 (copper/zinc superoxide dismutase) and Sesn1 (sestrin 1) in the kidneys of recuperated offspring suggest that protein homoeostasis and resistance to oxidative stress are compromised, leading to accelerated cellular senescence in these shorter-lived mice.