Abnormality of Klotho Signaling Is Involved in Polycystic Ovary Syndrome

Abstract

This study investigated the involvement of the klotho-associated signaling in the apoptosis of granulosa cells (GCs) from the ovaries of patients with polycystic ovary syndrome (PCOS) and PCOS animals. Primary GCs were obtained from 26 healthy women and 43 women with PCOS. The PCOS animal model was established by the injection of dehydroepiandrosterone (DHEA). Klotho protein and associated microRNA expression in human primary GCs and rats' ovarian tissues were measured by Western blot and real-time polymerase chain reaction, respectively. Results showed that significantly lower miR-126-5p and miR-29a-5p microRNA expressions, higher klotho protein expression, lower insulin growth factor 1 (IGF-1R) and Wnt family member 1 (Wnt1) protein expressions, and lower Akt phosphorylation at Ser and Thr residues were observed in the GCs from patients with PCOS and the ovarian tissues of PCOS rats compared to that in GCs from healthy women and ovarian tissues of normal control rats, respectively. Knockdown of klotho gene expression normalized IGF-1R and Wnt1 protein expressions and Akt phosphorylation in GCs from patients with PCOS and the ovarian tissues from PCOS rats; it also blocked the effects of insulin on apoptosis and proliferation in GCs from patients with PCOS and inhibited caspase-3 activity in ovarian tissues of PCOS rats. Knockdown of klotho gene expression increased the pregnancy rate in DHEA-treated female rats and increased the body weight of their newborns through normalizing the ovarian function and decreasing the formation of cystic follicles. In conclusion, the miR-126-5p, miR-29a-5p/klotho/insulin-IGF-1, Wnt, and Akt signal pathway may be involved in the apoptosis of GCs and subsequent development of PCOS.

Dynamics of the Transcriptome and Accessible Chromatin Landscapes During Early Goose Ovarian Development

“…Several top enriched GO-BP terms and/or KEGG pathways by either these DEGs or genes around differential peaks were related to ligand-receptor interaction, tissue remodeling, signal transduction, and metabolic processes, most of which were reported to be associated with the formation and development of mammalian ovarian primordial follicles (Smith et al, 2002;Nilsson et al, 2010;Hu et al, 2019). Among nearby DEGs of differential chromatin accessibility, only the SLC2A11 and klotho (KL) genes were shown to be possibly involved in regulating mammalian ovarian activities (Mao et al, 2018;Hu et al, 2019) while others have been largely implicated in regulating cancer cell proliferation and apoptosis. Furthermore, our quantitative results verified that the mRNA levels of KL decreased continuously during early goose ovarian development, which may be indicative of its inhibitory actions in primordial follicle formation and subsequent progression to secondary follicles.…”

MiR-126-3p inhibits apoptosis and promotes proliferation by targeting phosphatidylinositol 3-kinase regulatory subunit 2 in porcine ovarian granulosa cells

“…A recent study has reported that miR-126-5p is significantly decreased in GCs of polycystic ovarian syndrome (PCOS) patients, compared to healthy women, and may be involved in GC apoptosis [20]. In our previous study, we have proved that miR-126-3p inhibits apoptosis and promotes proliferation of porcine ovarian GCs [21].…”

Variants in BMP7 and BMP15 3’-UTRs Associated with Reproductive Traits in a Large White Pig Population

“…MREs are sequences in the 3’- UTR of mRNAs that recognize the seed region on the miRNA, thereby mediating direct interactions between the miRNA and its target mRNA [16,17]. Importantly, several putative BMP7 - or BMP15 -targeted miRNAs, such as miR-17-3p [18], miR-21-3p [19], miR-29a-5p [20], and miR-132-5p [21], have been demonstrated to be related to reproduction [22,23]. The ARE motif, an important cis -element for RNA regulation, is involved in RNA processing, transport, and translation through its interaction with ARE-binding proteins, such as the tristetraprolin (TTP), heterogeneous nuclear ribonucleoprotein D (HNRPD; also AUF1), ELAV-like RNA-binding protein 1 (ELAV1; also HuR), and KH-type splicing regulatory protein (KSRPH) [24,25].…”