Transgenerational programming of nephron deficits and hypertension

Exposure to a sub-optimal environment in the womb can result in poor fetal growth and impair the normal development of organs. The kidney, specifically the process of nephrogenesis, has been shown to be impacted by many common pregnancy exposures including an inadequate diet, poor placental function, maternal stress as well as maternal smoking and alcohol consumption. This can result in offspring being born with a reduced nephron endowment, which places these individuals at increased risk of hypertension and chronic kidney disease (CKD). Of recent interest is whether this disease risk can be passed on to subsequent generations and, if so, what are the mechanisms and pathways involved. In this review, we highlight the growing body of evidence that a low birth weight and hypertension, which are both major risk factors for cardiovascular and CKD, can be transmitted across generations. However, as yet there is little data as to whether a low nephron endowment contributes to this disease transmission. The emerging data suggests transmission can occur both through both the maternal and paternal lines, which likely involves epigenetic mechanisms such chromatin remodelling (DNA methylation and histone modification) and non-coding RNA modifications. In addition, females who were born small and/or have a low nephron endowment are at an increased risk for pregnancy complications, which can influence the growth and development of the next generation. Future animal studies in this area should include examining nephron endowment across multiple generations and determining adult renal function. Clinically, long term follow-up studies of large birth cohorts need to be undertaken to more clearly determine the impact a sub-optimal environment in one generation has on the health outcomes in the second, and subsequent, generation.