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Kidney Week

Abstract: FR-PO778

Ontogeny and Phylogeny: Our Evolutionary History and Bioenergetics Explain High Variation in Nephron Number (NN) at Birth

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 500 Development, Stem Cells, and Regenerative Medicine

Author

  • Chevalier, Robert L., University of Virginia, Charlottesville, Virginia, United States
Background

Low NN at birth is recognized as a major lifetime risk factor for chronic kidney disease (CKD), but its origin is poorly understood. Recent studies based on the Barker hypothesis suggest that epigenetic downregulation of nephrogenesis modulated by maternal-fetal stressors (e.g. hypoxia, undernutrition) contributes to CKD in adulthood. Application of evolutionary biology to medicine has led to new approaches in cancer and infectious disease research, and shows promise in nephrology (Chevalier, Kidney Int Rep 2:302, 2017; J Am Soc Nephrol 29:705, 2018).

Methods

Data abstraction: Medline searches including the terms “kidney, evolution, physiology, genetics, bioenergetics, and development” 1970 to the present.

Results

The rapid evolution of hominids was a product of increased nutrient quality and availability ~2 million years ago, resulting from transition of the east African environment from forest to savannah. Natural selection favored doubling brain size from Homo habilis to Homo sapiens over a period of 1 million years. Our brain consumes 90% of basal metabolic rate (BMR) at birth, 50% at 1 year of age, and 20% in adulthood. Maternal energy consumption in pregnancy and during breastfeeding increases BMR by 20%, which must be balanced by high kidney oxygen consumption tied to BMR. Maternal protein restriction during pregnancy in mice resulted in 75% reduction in NN; offspring of mice lacking DNA methyltransferase 1 (Dmt1) in nephron progenitor cells developed 50% reduction in NN. Nutrients and oxygen signal energy metabolism to mitochondria through the hypoxia-inducible factor (HIF) pathway to regulate nephron morphogenesis. This epigenetic response is driven by metabolic reprogramming of nephron progenitor cells from glycolysis (maintenance of self-renewal) to differentiation (cessation of nephrogenesis) mediated by the Wnt pathway.

Conclusion

Energy, the currency of evolution, is constrained by the environment. Selection pressure favors allocation of available energy from kidney to brain growth in early development. Through epigenetic regulation of bioenergetics, reduction of nutrients available during pregnancy proportionately restricts nephrogenesis. Since only 18% of children with congenital kidney anomalies develop end-stage CKD before 15 years of age, this evolutionary strategy favors reproductive fitness in the majority of cases.