HIF involvement in the regulation of rat Sertoli cell proliferation by FSH

The final number of Sertoli cells reached during the proliferative periods determines sperm production capacity in adulthood. It is well known that FSH increases the rate of proliferation of Sertoli cells; however, little is known about the transcription factors that are activated by the hormone in order to regulate Sertoli cell proliferation. On the other hand, Hypoxia Inducible Factors (HIFs) are master regulators of cell growth. HIFs are dimers of HIF-beta and HIF-alpha subunits. Considering that HIF-beta is constitutively expressed, HIF transcriptional activity is regulated through the abundance of HIF-alpha subunits. To date, three HIF-alpha isoforms have been described. The association of the different HIF-alpha subunits with HIF-beta subunit constitutes three active transcription factors -HIF-1, HIF-2 and HIF-3- which interact with consensus hypoxia-response elements in the promoter region of target genes. Hypoxia has been classically considered the main stimulus that increases HIF transcriptional activity, however, regulation by hormones under normoxic conditions was also demonstrated. The aim of this work has been to investigate whether HIFs participate in the regulation of rat Sertoli cell proliferation by FSH. Sertoli cells obtained from 8-day old rats were cultured in the absence or presence of FSH. It has been observed that FSH increases HIF transcriptional activity and HIF-2 alpha mRNA levels without modifying either HIF-1 alpha or HIF-3 alpha expression. Incubations with FSH have been also performed in the absence or presence of a pharmacological agent that promotes HIF-alpha subunit degradation, LW6. It has been observed that LW6 inhibits the FSH effect on proliferation, CCND1 expression and c-Myc transcriptional activity. Altogether, these results suggest that HIFs might be involved in the regulation of Sertoli cell proliferation by FSH. (C) 2018 Elsevier Inc. All rights reserved.