The ageing kidney remembers its nutritional beginnings

Abstract

The developmental origins of chronic diseases, including hypertension and chronic kidney disease, are now widely accepted. Early epidemiological observations linking impaired fetal and infant growth with later cardiovascular disease helped to establish this concept. Subsequent experimental studies demonstrated that maternal protein restriction can have lasting effects on nephron endowment, blood pressure and renal haemodynamics (Lamana et al., 2021; Woods et al., 2001). Much of the evidence has therefore been framed in physiological and morphological terms. Although the cellular and molecular programmes governing nephrogenesis are increasingly well defined, considerably less is known about how nutritional adversity becomes embedded within the kidney and alters its response to ageing, although recent work has made significant progress in defining how a maternal low-protein diet perturbs nephron progenitor differentiation into nephrons during fetal development (Short et al., 2026). The study by Pires and colleagues in this issue of The Journal of Physiology now extends this molecular perspective into ageing, revealing that the aged kidney retains a molecular memory of early protein restriction, marked by metabolic and redox remodelling alongside tubular injury and changes in the extracellular matrix.

Pires et al., (2026) examined the effects of maternal protein restriction in rats by feeding dams either a 6% protein diet or a 17% protein control diet throughout gestation and lactation. The study focused on male offspring, and both cohorts received a normal diet post weaning. This design allowed late-life renal changes to be interpreted as a legacy of early nutritional exposure rather than ongoing protein deprivation. Their study combined renal histopathology, circulating biochemical measures, whole-kidney proteomics and computational pathway analyses. The aged kidneys displayed structural abnormalities and elevated circulating creatinine, consistent with renal impairment. Whole-kidney proteomics revealed broad remodelling of mitochondrial metabolism, redox regulation, small-molecule transport and cellular stress responses. At the same time, proteins associated with cytoskeletal organisation, vesicular transport, extracellular processes and immune regulation were reduced. Together, these findings suggest that maternal protein restriction does not leave a single molecular lesion. Rather, it produces persistent changes in how the kidney manages energy demand, cellular organisation and tissue maintenance during ageing. The study therefore extends developmental programming beyond the familiar end points of reduced nephron endowment and altered blood pressure, showing that early nutritional adversity remains detectable in the molecular physiology of the aged kidney.

A particular strength of the study is the convergence between pathology and proteomics. Tubular atrophy, congestion, vacuolisation and extracellular matrix remodelling provide a structural context for the altered metabolic and stress-response pathways. The prominence of glycolysis, pyruvate metabolism, the tricarboxylic acid cycle, amino acid and fatty acid metabolism and antioxidant defence is consistent with a kidney operating under sustained metabolic pressure. Earlier physiological studies identified glomerular hyperfiltration, reduced renal blood flow and altered proximal tubular sodium handling after maternal protein restriction, providing plausible routes by which a developmentally constrained kidney might face increased energetic demand throughout life (Lamana et al., 2021). Whether the proteomic signature observed by Pires et al., (2026) represents successful compensation, progressive maladaptation or a transition between the two cannot be resolved from a single late-life time point. Nevertheless, the findings provide a molecular framework for understanding how a kidney formed under nutritional constraint might become less resilient with age.

An especially intriguing perspective emerges when the study is considered alongside the related analysis by Alvarez et al., (2026) in post-weaning male offspring. At that earlier time point, maternal protein restriction was associated with reduced representation of proteins involved in energy metabolism, ion transport and mitochondrial function. In the aged kidneys studied by Pires et al., (2026), many proteins and pathways associated with glycolysis, mitochondrial respiration, amino acid metabolism and antioxidant defence were instead increased. Several metabolic proteins were identified across both life stages, in some cases with altered direction of expression. Separate cross-sectional studies cannot establish a temporal sequence, and differences in cohorts or analysis might also contribute. Even so, the contrast raises a testable possibility, in that an early deficit in metabolic capacity might be followed by compensatory activation and, with ageing, metabolic strain. Longitudinal studies will be required to distinguish molecular persistence from age-dependent adaptation.

The computational meta-analyses using mouse sequencing data extend the whole-kidney proteomic findings by mapping selected up- or downregulated protein candidates onto nephron and renal cell populations and identifying potential regulatory and disease-associated networks. This draws attention to tubular regions in which altered mitochondrial, amino acid and lipid metabolism could have substantial physiological consequences. Pires et al., (2026) suggest the potential for microRNA interactions; however, they present no experimental evidence to substantiate the claim. Moreover, because protein abundance was measured in whole kidney, the analysis cannot distinguish cell-intrinsic regulation from changes in cellular or tissue composition. These analyses therefore provide valuable hypotheses rather than direct evidence of segment-specific protein regulation. Direct measurements of filtration, tubular transport and urinary injury markers, together with spatial or segment-resolved proteomics, will be needed to determine how the molecular signatures translate into renal physiology. The restriction of the study to male offspring leaves the influence of sex on renal ageing after maternal protein restriction unresolved.

Taken together, Pires et al., (2026) shift the question from whether an adverse nutritional environment alters the developing kidney to how a developmentally programmed kidney subsequently ages. Their integration of pathology and proteomics suggests that structural injury, metabolic adaptation and declining renal resilience might be interconnected consequences of early nutritional adversity. The kidney might therefore do more than retain a molecular memory of its beginnings; it might spend a lifetime adapting to them.