Developmental Programming of Renal Function and Re-Programming Approaches

Abstract

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.

AMP-Activated Protein Kinase as a Reprogramming Strategy for Hypertension and Kidney Disease of Developmental Origin

“…Reprogramming strategies to counterbalance the programming processes that have been employed range from nutritional intervention and lifestyle modification to pharmacological therapy [ 1 , 5 , 50 ]. Currently, a variety of therapeutic regimens have been reported to either activate or inhibit AMPK activity and its downstream signaling pathway.…”

Altered molecular signatures during kidney development after intrauterine growth restriction of different origins

“…Insufficient intrauterine nutrient supply induces intrauterine growth restriction (IUGR) and is a major cause of low birth weight [1,2,4,5]. Concerning renal outcome, IUGR may predispose to an unfavorable course of glomerulopathies, arterial hypertension, and decreased renal function and an elevated risk of end-stage renal disease in young adulthood [6][7][8][9][10][11][12].…”

Clinical consequences of developmental programming of low nephron number

“…Programmed alterations in the expression of renal sodium transporters, activity of the renin-angiotensin system and of the sympathetic nervous system have also been reported, which likely contribute to the risk of hypertension in programmed animals (Nuyt and Alexander, 2009;Baum, 2010;Kett and Denton, 2011;Nuyt et al, 2017;Luyckx et al, 2019). Developmental programming in the kidney is therefore complex, but experimental data do suggest potential windows for early intervention that could abrogate long-term risk of hypertension and kidney disease (Nusken et al, 2018).…”