Testosterone exposure during fetal masculinization programming window determines the kidney size in adult mice.
Junnila, A.; Rytkonen, K. T.; Martinez-Nieto, G.; Perk, M.; Li, H.; Airaksinen, J.; Hyotylainen, I.; Mehtovuori, O.; Laiho, A.; Ohlsson, C.; Elo, L. L.; Kuure, S.; Poutanen, M.; Sipila, P.
Show abstract
Kidney size is sex-dimorphic and regulated by androgens in adult humans and mice. However, the effects of developmental androgen deficiency on kidneys remain elusive. We hypothesized that androgens program future kidney growth during a fetal development. Male mice lacking main testosterone-producing enzyme HSD17B3 had reduced testosterone at embryonic day 15.5, but the concentrations increased by E18.5, creating a short time window of androgen deficiency resulting in reduced kidney size in adult males. In male Hsd17b3-/-kidneys, nephron development was qualitatively normal, but number of glomeruli and proliferation of proximal tubules was reduced. Testosterone supplementation at E14.5-17.5 normalized the renal size in adult Hsd17b3-/-males. Our data suggests that androgen receptor and Hnf4a jointly regulate Igfbp5, FOXO1 and mTOR signaling to convey male-specific kidney growth. In conclusion, we have identified a novel developmental programming effect on male kidneys, where fetal androgen deficiency reduces kidney growth and androgen responsiveness in adult males.
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