Maternal protein restriction programs the ageing kidney: Proteomic signatures of early‐life origin renal and metabolic dysfunction

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The Developmental Origins of Health and Disease framework proposes that adverse exposures during critical developmental windows induce epigenetic programming, increasing lifelong risk of metabolic and organ dysfunction. Maternal protein restriction (MPR) is a well-established model of early-life nutritional stress, associated with reduced nephron number early in life, in addition to renal dysfunction and hypertension during adult life. However, its long-term impact on renal ageing remains unclear. This study investigated the effects of gestational and lactational severe MPR (6% compared to 17% in controls) on the renal proteome of aged male Sprague-Dawley rats (postnatal day 540) using integrated histological, molecular and in silico approaches. MPR induced persistent renal impairment, evidenced by increased serum creatinine and tubular congestion. Proteomic analysis revealed upregulation of proteins related to small-molecule transport, stress response and energy metabolism, particularly within mitochondrial and redox pathways. By contrast, downregulated pathways involved cytoskeletal organization, vesicular transport, immune processes and post-transcriptional regulation, suggesting disruption of endomembrane dynamics. Pathway enrichment highlighted central metabolic networks, including glycolysis, pyruvate metabolism and the tricarboxylic acid cycle. Network and microRNA analyses indicated epigenetic regulation, whereas disease enrichment linked findings to metabolic and renal disorders. Nephron-segment mapping revealed region-specific alterations. Overall, MPR induces persistent renal programming, disrupting metabolism and function and increasing susceptibility to renal and metabolic diseases with ageing. KEY POINTS: Maternal protein restriction (MPR) shifts renal proteome to mitochondrial/redox metabolism. MPR causes renal histopathological lesions during ageing. The impacts of MPR are reflected in cellular and molecular alterations indicative of potential renal dysfunction. Nephron-specific and epigenetic alterations indicate targeted functional disruption. Persistent changes link early malnutrition to renal and metabolic disease risk.