In mammalian kidneys nephrogenesis is completed before or shortly after birth and nephron number subsequently decreases throughout life. New data from Oded Volovelsky, Raphael Kopan and colleagues suggest a role of hamartin in determining initial nephron number. This protein, which is encoded by Tsc1, is an inhibitor of mammalian target of rapamycin (mTOR).
“A non-ideal environment of kidney development in the embryo or a disease of the kidney such as pyelonephritis or glomerulonephritis in childhood reduces the nephron reserve so significantly increases the risk of chronic kidney disease in adulthood,” explains Volovelsky. “Our goal is to find a way to give children the best background to cope with kidney disease in adulthood resulting from diabetes, obesity and high blood pressure. This goal can be achieved by reducing risk factors for prematurity or malnutrition during pregnancy and by identifying the mechanisms that determine initial nephron numbers, which was the focus of our recent study.”
The researchers show that in mice complete loss of mTOR in nephron progenitor cells (NPCs) resulted in failure to develop a functional kidney, whereas loss of one mTOR allele led to a significant decrease in nephron count. By contrast, NPC-specific deletion of Tsc1 resulted in severe tubular lesions but normal glomeruli, whereas loss of one Tsc1 allele prolonged nephrogenesis, leading to a significant increase in nephron number with no apparent adverse effects. The Tsc1 phenotypes were dependent on the scaffold protein Raptor but independent of mTOR activity.
“Hamartin has an mTOR-independent role in determining the timing of cessation of nephrogenesis, and thus nephron number,” concludes Kopan. “We are now trying to decipher the mechanism and hope to identify druggable targets to enable us to start marching on the long road leading to clinical interventions to maximize initial nephron numbers in premature babies and other at-risk populations.”
Volovelsky, O. et al. Hamartin regulates cessation of mouse nephrogenesis independently of Mtor. Proc. Natl. Acad. Sci. USA https://doi.org/10.1073/pnas.1712955115 (2018)