ESPN 54th Annual Meeting

ESPN 2022


 
The sexual dimorphism of kidney growth in mice and humans
PAUL VERGNAUD 1 DENISE LAOUARI 1 TAKUO HIROSE 1 MARION RABANT 1 MOHAMAD ZAIDAN 1 CLEMENT NGUYEN 1 MARTINE BURTIN 1 CHRISTOPHE LEGENDRE 1 PATRICE CODOGNO 1 GERARD FRIEDLANDER 1 DANY ANGLICHEAU 1 FABIOLA TERZI 1

1- INSTITUT NECKER ENFANTS MALADES
 
Introduction:

Kidney mass and function are sexually determined but the cellular events and the molecular mechanisms involved in this dimorphism are poorly characterized. The objective of this study was to elucidate them.

Material and methods:

We combined in vivo approaches with female and male mice and castration/replacement experiments with in vitroapproaches with renal tubular cells treated with dihydrotestosterone or vehicle.

Results:

We showed that males exhibited kidney overgrowth from five weeks of age. This effect was organ-specific, since liver and heart weight were comparable between males and females, regardless of age. Consistently, androgen receptor was expressed in male kidney, but not in liver. In growing mice, androgens led to kidney overgrowth by first inducing a burst of cell proliferation and then an increase of cell size. Remarkably, androgens were also required to maintain cell size in adults. In fact, orchiectomy resulted in smaller kidneys in a matter of few weeks. These changes paralleled the changes of the expression of ornithine decarboxylase and cyclin D1, two known mediators of kidney growth, whereas, unexpectedly, mTORC1 and Hippo pathways did not seem to be involved. Androgens also enhanced in vivo and in vitro renal autophagy, very likely by increasing TFEB nuclear translocation. Functionally, the increase of tubular mass resulted in increased sodium/phosphate transport. These findings were relevant to humans. Indeed, by studying living gender-paired kidney donors-recipients, we showed that tubular cell size increased three months after transplantation in men as compared to women, regardless of the donor gender.

Conclusions:

Collectively, these results identify novel signaling pathways that may be involved in androgens-induced kidney growth and homeostasis and suggest that androgens determine kidney size during physiological growth and after transplantation. Thus, targeting these pathways might lead to the development of novel therapeutic strategies for kidney transplantation.