The Impact of Low-Protein Diet on the Molecular and Cellular Development of the Fetal Kidney
- Author(s)
- Short, KM; Tortelote, GG; Jones, LK; Diniz, F; Edgington-Giordano, F; Cullen-McEwen, LA; Schröder, J; Spencer, A; Keniry, A; Polo, JM; BERTRAM, JF; Blewitt, ME; Smyth, IM; El-Dahr, SS;
- Journal Title
- Journal of the American Society of Nephrology
- Publication Type
- Mar 26
- Abstract
- BACKGROUND: Low nephron number has a direct impact on the development of hypertension and chronic kidney disease later in life. While intrauterine growth restriction caused by maternal low-protein diet (LPD) is thought to be a significant cause of reduced nephron endowment in impoverished communities, its influence on the cellular and molecular processes which drive nephron formation are poorly understood. METHODS: We conducted a comprehensive characterization of the impact of LPD on kidney development using tomographic and confocal imaging to quantify changes in branching morphogenesis and the cellular and morphological features of nephrogenic niches across development. These analyses were paired with single-cell RNA sequencing to dissect the transcriptional changes that LPD imposes during development of the kidneys to affect nephron number. RESULTS: Single-cell analysis revealed differential expression across metabolic, cell-cycle, epigenetic, and reciprocal inductive signaling pathways in most cell types, shifting cellular energy production and developmental trajectories. In nephron progenitor cells, LPD impeded commitment and differentiation toward pre-tubular aggregates and renal vesicles, accompanied by downregulated Wnt signaling. Confocal microscopy showed fewer pre-tubular aggregates and reduced progenitor proliferation, consistent with impaired commitment. Critically, nephron progenitor cell proliferation remained reduced through P0, whereas ureteric tip proliferation, although reduced earlier, had normalized by P0. Branching morphology also changed, with optical projection tomography showing shorter tip and tip-parent lengths, consistent with subtle patterning defects. CONCLUSIONS: This study demonstrates that gestational low-protein diet reduces nephron endowment by impairing nephron progenitor cell commitment, with concurrent alterations in branching morphogenesis. These findings position disrupted progenitor commitment as a central developmental mechanism underlying nephron deficit in this model.
- Publisher
- ASN
- Research Division(s)
- Genetics and Gene Regulation
- PubMed ID
- 41885952
- Publisher's Version
- https://doi.org/10.1681/asn.0000001053
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2026-04-27 02:50:42
Last Modified: 2026-04-27 02:50:51