Epigenetic Regulation of Nephrogenesis: From Waddington's Landscape to Adult Disease.

The establishment of lifelong nephron endowment depends on the tightly coordinated regulation of nephron progenitor cell (NPC) self-renewal, lineage specification, and differentiation during kidney development. Conrad H. Waddington's developmental landscape provides a powerful conceptual framework for understanding how NPCs navigate sequential fate decisions toward mature renal epithelial identities. Within this paradigm, the topology of the landscape is actively shaped by epigenetic mechanisms, including DNA methylation, histone post-translational modifications, non-coding RNA-mediated gene regulation, and higher-order chromatin organization, which collectively control the timing, location, duration, and strength of gene expression programs that direct nephrogenesis. Under normal conditions, these epigenetic programs preserve progenitor competence while progressively stabilizing lineage commitment and nephron patterning. When disrupted, however, they impair progenitor plasticity, accelerate NPC pool depletion, and ultimately reduce nephron number. Such maladaptive epigenetic reprogramming establishes a mechanistic link between adverse intrauterine environments and lifelong susceptibility to hypertension and chronic kidney disease. In this review, we revisit Waddington's landscape in the context of renal development and integrate emerging insights from developmental biology, cell metabolism, and epigenomics to examine how early-life environmental perturbations durably reshape the nephrogenic program and increase the risk of adult-onset kidney disease.