Developmental origins of hypertension and renal injury: epigenetic memory in renal stem and progenitor cells.

The developmental origins of health and disease (DOHaD) theory proposes that environmental exposure during critical periods of fetal and early postnatal development induces long-lasting biological changes that shape health trajectories across the lifespan. Hypertension and renal injury are adult-onset conditions associated with developmental programming that may increase the risk of non-communicable diseases later in life. Traditionally, reduced nephron endowment and subsequent glomerular hyperfiltration have been considered the principal mechanisms linking adverse fetal environments to subsequent hypertension and kidney disease. However, this paradigm does not fully explain the delayed onset or heterogeneity of these conditions. Accumulating evidence indicates that epigenetic regulation is a key mechanism by which early-life adversity is recorded. Renal stem and progenitor cells have emerged as cellular substrates for developmental programming, retaining information acquired during organogenesis, and influencing renal and vascular homeostasis later in life. Experimental studies have suggested that fetal malnutrition induces persistent epigenetic alterations in these cells, leading to altered differentiation, impaired repair capacity, and dysregulation of the intrarenal renin-angiotensin system, thereby increasing susceptibility to hypertension and renal injury in adulthood. Additionally, metabolic programming may interact with epigenetic regulation through sustained alterations in mitochondrial function and key metabolites. This mini-review summarizes the current evidence linking developmental programming to hypertension and renal injury, focusing on epigenetic regulation in renal stem and progenitor cells and metabolic alterations observed at the renal tissue level. We also discuss the reversibility, clinical implications for early life surveillance, and future directions for life-course strategies to prevent hypertension and renal injury. Graphical abstract. Developmental programming of hypertension and renal injury: epigenetic and metabolic memory. Adverse early-life environments, including fetal malnutrition, fetal growth restriction, ischemia, and prematurity, may program epigenetic memory in renal stem and progenitor cells and metabolic alterations in renal tissue. Epigenetic-metabolic interactions contribute to persistent abnormalities in renal mesenchymal stem cell (MSC) differentiation, intrarenal renin-angiotensin system (RAS) activation, injury-induced activation of label-retaining cells (LRCs), and endothelial progenitor cell (EPC)-mediated vascular repair. Postnatal nutrition, high salt intake, obesity, kidney injury, and ageing may amplify this vulnerability, promoting adult hypertension and renal injury and increasing long-term susceptibility to CKD. Maternal nutrition and supplementation, early surveillance, and lifestyle intervention represent potentially modifiable windows across the life course.