The Impact of Low-Protein Diet on the Molecular and Cellular Development of the Fetal Kidney

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KEY POINTS: Maternal low protein diet reduced kidney size and altered branching without changing ureteric tip number, with fewer nephrons at birth and adulthood. Nephron progenitor proliferation and commitment were impaired, pretubular aggregate formation decreased, consistent with a reduced nephron number. BACKGROUND: Low nephron number has a direct effect on the development of hypertension and CKD later in life. Although intrauterine growth restriction caused by maternal low-protein diet (LPD) is believed to be a significant cause of reduced nephron endowment in impoverished communities, its influence on the cellular and molecular processes that drive nephron formation are poorly understood. METHODS: We conducted a comprehensive characterization of the effect of LPD on kidney development using tomographic and confocal imaging to quantify changes in branching morphogenesis and the cellular and morphologic 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 pretubular aggregates and renal vesicles, accompanied by downregulated Wnt signaling. Confocal microscopy showed fewer pretubular 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 LPD reduced nephron endowment by impairing nephron progenitor cell commitment, with concurrent alterations in branching morphogenesis.

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