Renal proteomics of male offspring exposed to maternal protein restriction: molecular, epigenetic, and nephron-specific signatures of metabolic programming.

Chronic kidney disease is an increasing global public health concern, and the Developmental Origins of Health and Disease (DOHaD) concept proposes that adverse conditions during critical developmental windows predispose offspring to chronic disorders later in life. Maternal protein restriction (MPR), a well-established experimental model reflecting food insecurity, has been shown to impair nephrogenesis and promote long-term renal dysfunction. In this study, we investigated renal metabolic-epigenetic programming induced by gestational and lactational MPR in post-weaning male rats using a global kidney proteomic approach. MPR altered renal structure and profoundly dysregulated protein networks, characterized by downregulation of energy metabolism, ion transport, cytoskeletal organization, membrane integrity, and mitochondrial function, alongside upregulation of innate immune pathways, glutathione metabolism, vesicular trafficking, and cytoskeletal dynamics. Integrated pathway and disease enrichment analyses revealed the potential risk to hypertension, acid-base imbalance, renal tubular transport disorders, nephrosis, and renal failure. Key differentially expressed proteins (e.g., GPX1, CYCS, ATP1A2/ATP1B1, TUBB/TUBA isoforms, ANPEP, and metabolic enzymes) emerged as potential biomarkers of renal metabolic-epigenetic programming. Collectively, these findings identify molecular signatures that link early-life protein restriction to long-term risk of kidney disease and provide mechanistic insight into the nephron- and cell-specific consequences of MPR.