Developmental Programming of Renal Function and Re-Programming Approaches

Chronic kidney disease affects more than 10% of the population. Programming studies have examined the interrelationship between environmental factors in early life and differences in morbidity and mortality between individuals. A number of important principles has been identified, namely permanent structural modifications of organs and cells, long-lasting adjustments of endocrine regulatory circuits, as well as altered gene transcription. Risk factors include intrauterine deficiencies by disturbed placental function or maternal malnutrition, prematurity, intrauterine and postnatal stress, intrauterine and postnatal overnutrition, as well as dietary dysbalances in postnatal life. This mini-review discusses critical developmental periods and long-term sequelae of renal programming in humans and presents studies examining the underlying mechanisms as well as interventional approaches to “re-program” renal susceptibility toward disease. Clinical manifestations of programmed kidney disease include arterial hypertension, proteinuria, aggravation of inflammatory glomerular disease, and loss of kidney function. Nephron number, regulation of the renin–angiotensin–aldosterone system, renal sodium transport, vasomotor and endothelial function, myogenic response, and tubuloglomerular feedback have been identified as being vulnerable to environmental factors. Oxidative stress levels, metabolic pathways, including insulin, leptin, steroids, and arachidonic acid, DNA methylation, and histone configuration may be significantly altered by adverse environmental conditions. Studies on re-programming interventions focused on dietary or anti-oxidative approaches so far. Further studies that broaden our understanding of renal programming mechanisms are needed to ultimately develop preventive strategies. Targeted re-programming interventions in animal models focusing on known mechanisms will contribute to new concepts which finally will have to be translated to human application. Early nutritional concepts with specific modifications in macro- or micronutrients are among the most promising approaches to improve future renal health

No juvenile arterial hypertension in sheep multiples despite reduced nephron numbers

Low birth weight is associated with an increased risk of metabolic dysfunction and arterial hypertension in later life. Because of their reduced birth weight twins have been used repeatedly as a natural model to investigate prenatal programming of hypertension. To reveal an early impact of lower nephron endowment on blood pressure, we performed a longitudinal study on lambs from single, twin and triplet pregnancies. The lambs were studied from birth until adulthood, including regular blood analyses, measurements of body weight and blood pressure and post-mortem estimation of glomerular numbers. Relative weight differences between multiples and singletons at birth were −28% for twins and −44% for triplets, respectively. Some lambs showed rapid catch-up growth. Total nephron number of twins and triplets was reduced by 21 and 37% with respect to that of singletons (p < 0.01). However, multiples did not show increased blood pressure within the time frame of this study. No gender-specific effect was observed. Plasma concentrations of creatinine, urea, electrolytes or osmolality also did not differ. Our data indicate that the previously reported postnatal blood pressure differences between sheep multiples and singletons are a time-limited phenomenon. During infancy and adolescence, a reduced nephron number in sheep multiples is neither associated with increased blood pressure nor reflected by plasma parameters

Perinatal Obesity Sensitizes for Premature Kidney Aging Signaling

Chronic Kidney Disease (CKD), a global health burden, is strongly associated with age-related renal function decline, hypertension, and diabetes, which are all frequent consequences of obesity. Despite extensive studies, the mechanisms determining susceptibility to CKD remain insufficiently understood. Clinical evidence together with prior studies from our group showed that perinatal metabolic disorders after intrauterine growth restriction or maternal obesity adversely affect kidney structure and function throughout life. Since obesity and aging processes converge in similar pathways we tested if perinatal obesity caused by high-fat diet (HFD)-fed dams sensitizes aging-associated mechanisms in kidneys of newborn mice. The results showed a marked increase of γH2AX-positive cells with elevated 8-Oxo-dG (RNA/DNA damage), both indicative of DNA damage response and oxidative stress. Using unbiased comprehensive transcriptomics we identified compartment-specific differentially-regulated signaling pathways in kidneys after perinatal obesity. Comparison of these data to transcriptomic data of naturally aged kidneys and prematurely aged kidneys of genetic modified mice with a hypomorphic allele of Ercc1, revealed similar signatures, e.g., inflammatory signaling. In a biochemical approach we validated pathways of inflammaging in the kidneys after perinatal obesity. Collectively, our initial findings demonstrate premature aging-associated processes as a consequence of perinatal obesity that could determine the susceptibility for CKD early in life