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Regulation of nephron progenitor cell lifespan and nephron endowment

Nature Reviews Nephrology volume 18, pages 683–695 (2022)Cite this article

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Abstract

Low nephron number — resulting, for example, from prematurity or developmental anomalies — is a risk factor for the development of hypertension, chronic kidney disease and kidney failure. Considerable interest therefore exists in the mechanisms that regulate nephron endowment and contribute to the premature cessation of nephrogenesis following preterm birth. The cessation of nephrogenesis in utero or shortly after birth is synchronized across multiple niches in all mammals, and is coupled with the exhaustion of nephron progenitor cells. Consequently, no nephrons are formed after the cessation of developmental nephrogenesis, and lifelong renal function therefore depends on the complement of nephrons generated during gestation. In humans, a tenfold variation in nephron endowment between individuals contributes to differences in susceptibility to kidney disease; however, the mechanisms underlying this variation are not yet clear. Salient advances in our understanding of environmental inputs, and of intrinsic molecular mechanisms that contribute to the regulation of cessation timing or nephron progenitor cell exhaustion, have the potential to inform interventions to enhance nephron endowment and improve lifelong kidney health for susceptible individuals.

Key points

  • Nephron endowment in humans varies more than tenfold between individuals, with consequences for susceptibility to chronic kidney disease and kidney failure.

  • Nephron endowment can be reduced or increased by modulation of nutritional inputs including gestational protein, fat and vitamin intake. Adaptation to prenatal nutrition may prove detrimental when the offspring’s adult environment differs from gestational conditions.

  • Numerous genes are required for maintenance of the self-renewing population; the reduction or loss of these genes in embryonic nephron progenitor cells can result in premature depletion of this progenitor population with consequent reduced nephron numbers.

  • Nephrogenesis cessation timing in mice is determined by a community effect and is tunable by altering the perception of WNT signalling strength by nephron progenitor cells to favour self-renewal versus differentiation.

  • The twofold range in nephron number observed between mouse strains could be leveraged to identify genetic loci that regulate nephron number variation. Optimization of methods to accurately evaluate nephron numbers in vivo will be of great value to future efforts.

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Fig. 1: Nephrogenesis in the mouse.
Fig. 2: Effect of nutritional status on nephron number.
Fig. 3: Model for determining the timing of nephrogenesis cessation.

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Authors and Affiliations

  1. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Alison J. Perl, Meredith P. Schuh & Raphael Kopan

  2. Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Alison J. Perl, Meredith P. Schuh & Raphael Kopan

  3. Division of Nephrology and Hypertension, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Meredith P. Schuh

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A.J.P. and R.K. contributed equally to all aspects of the article. M.P.S. contributed to the review of clinical topics and edited the manuscript before submission.

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Correspondence to Raphael Kopan.

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Glossary

Uteroplacental insufficiency

A condition of inadequate placental exchange of oxygen, nutrients and waste products.

Patent ductus arteriosus

Abnormal persistent connection between the aorta and pulmonary artery after birth.

Heterochronic transplantation

Experimental method involving co-injection of nephron progenitor cells isolated from mouse kidneys of different embryonic ages into the same young niche in kidney explants.

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Perl, A.J., Schuh, M.P. & Kopan, R. Regulation of nephron progenitor cell lifespan and nephron endowment. Nat Rev Nephrol 18, 683–695 (2022). https://doi.org/10.1038/s41581-022-00620-w

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