{"paper_id":"06571e5c-e6c3-4919-a70e-2769218caa1e","body_text":"ABSTRACT\nBackground Maternal protein restriction results in a 28% reduction in nephrogenic cells and nephron units in rodent offspring by the 17th day of gestation compared to adequate protein intake.\nAims The present study investigates the association between growth factor expression and some developmental pathways that contribute to nephron reduction during embryonic and fetal development.\nExperimental Design Pregnant C57BL/6-Tg and C57BL/6J mice were assigned to either normal protein intake (NP-17%) or low protein intake (LP-6%) groups. Body weight of male offspring and kidney growth factor expression were assessed on gestation days (GD) 14 and 18.\nResults On GD 14, LP pups exhibited a 4% higher body mass (0.1035 g) compared to NP pups (0.0995 g, p = 0.005). By GD 18, LP pups demonstrated a 4% decrease in body mass (0.939 g, p = 0.03) and a 10% increase in the number of cells per metanephric cap area. Three genes (Csf2, Il1b, Il2) were downregulated, while seven genes (Bmp2, Csf3, Fgf8, Gdnf, Bmp7, Fgf3, Ntf3) were upregulated. By GD 14, phagophores and autophagosomes in the ureteric bud increased by 197%, with further increases observed by GD 18. Bcl-2 expression increased significantly in ureteric bud cells, and mTOR activity was elevated by GD 18.\nConclusion Early gestational protein restriction modifies renal growth factor gene expression, influencing cell proliferation and autophagy, and may contribute to reduced nephron numbers by the 18th day of gestation.\nHIGHLIGHTS\nThis study examines the effects of a low-protein diet during pregnancy in mice and demonstrates a significant reduction in embryo-fetal body weight between gestational days 14 and 18.\nProtein restriction induces a distinct cellular pattern in the mesonephros, with a 21% increase in CAP cells at gestational day 14 (GD14), followed by a decrease by gestational day 18 (GD18) compared to offspring from mothers on a normal protein diet.\nAdditionally, increased expression levels of key growth factors essential for kidney development were observed at GD 14, comparing LP with NP intake during pregnancy.\nSeven genes were upregulated (Gdnf, Bmp2, Bmp7, Tgfα, Fgf8, Fgf3, Csf3, Ntf3), while three genes were downregulated (Csf2, Il1b, Il2).\nOverall, these findings indicate that gene regulation, autophagy, and mTOR signaling mechanisms significantly influence nephron numbers in response to gestational protein restriction beyond the 18th day of gestation.\nCompeting Interest Statement\nThe authors have declared no competing interest.\nABBREVIATIONS AND ACRONYMS\n- AngII\n- angiotensin II.\n- ANOVA\n- variance analysis.\n- AT1\n- type1 angiotensin receptor\n- AT2\n- type 2 angiotensin receptor\n- BU\n- Ureteral Bud\n- BW\n- body weight.\n- CAP\n- metanephric Cap\n- CEMIB\n- Multidisciplinary Center for Biological Research in Science in Laboratory Animals.\n- CEUA\n- Institutional Ethics Committee approved the experimental design for the use of animals.\n- CIBIO\n- Internal Biosafety Commission\n- CONCEA\n- Brazilian Council for Animal Experimentation\n- CREB\n- cAMP-responsive element-binding\n- DOHaD\n- Developmental Origins of Health and Disease\n- FGF\n- Fibroblast growth factors\n- GD\n- Days of gestation\n- GDNF\n- Glial cell line-derived neurotrophic factor\n- IUGR\n- intrauterine growth restriction\n- LP\n- low-protein intake.\n- MM\n- Metanephric Mesenchyme\n- mTOR\n- mammalian target of rapamycin.\n- NP\n- normal protein intake.\n- PFA\n- Paraformaldehyde\n- Wk\n- week","source_license":"CC-BY-4.0","license_restricted":false}