Nephron progenitor cell death elicits a limited compensatory response associated
with interstitial expansion in the neonatal kidney.
Authors Muthukrishnan SD, Ryzhov S, Karolak M, Oxburgh L
Submitted By Leif Oxburgh on 2/20/2018
Status Published
Journal Disease models & mechanisms
Year 2018
Date Published 1/1/2018
Volume : Pages 11 : Not Specified
PubMed Reference 29196442
Abstract The final nephron number in an adult kidney is regulated by nephron progenitor
cell availability and collecting duct branching in the fetal period. Fetal
environmental perturbations that cause reductions in cell numbers in these two
compartments result in low nephron endowment. Previous work has shown that
maternal dietary factors influence nephron progenitor cell availability, with
both caloric restriction and protein deprivation leading to reduced cell numbers
through apoptosis. In this study, we evaluate the consequences of inducing
nephron progenitor cell death on progenitor niche dynamics and on nephron
endowment. Depletion of approximately 40% of nephron progenitor cells by
expression of diphtheria toxin A at embryonic day 15 in the mouse results in
10-20% nephron reduction in the neonatal period. Analysis of cell numbers within
the progenitor cell pool following induction of apoptosis reveals a compensatory
response in which surviving progenitor cells increase their proliferation and
replenish the niche. The proliferative response is temporally associated with
infiltration of macrophages into the nephrogenic zone. Colony stimulating factor
1 (CSF1) has a mitogenic effect on nephron progenitor cells, providing a
potential explanation for the compensatory proliferation. However, CSF1 also
promotes interstitial cell proliferation, and the compensatory response is
associated with interstitial expansion in recovering kidneys which can be
pharmacologically inhibited by treatment with clodronate liposomes. Our findings
suggest that the fetal kidney employs a macrophage-dependent compensatory
regenerative mechanism to respond to acute injury caused by death of nephron
progenitor cells, but that this regenerative response is associated with
neonatal interstitial expansion.