Kisspeptin regulates the proliferation and apoptosis of ovary granulosa cells in polycystic ovary syndrome by modulating the PI3K/AKT/ERK signalling pathway

Abstract

Background The development of polycystic ovary syndrome (PCOS) is closely correlated with apoptosis and oxidative stress in ovarian granulosa cells. Kisspeptin plays an important role in reproductive organ function. This study aimed to explore the role of kisspeptin in PCOS and oxidative stress-triggered apoptosis of ovarian granular cells. Methods A PCOS rat model was established by injecting dehydroepiandrosterone (DHEA) and feeding the rats a high-fat diet. The RNA and protein levels of kisspeptin were analysed by quantitative PCR, western blotting, and histological staining. Tissue damage was evaluated using haematoxylin and eosin (H&E) staining. The viability and proliferation of human granulosa cell KGN were measured using the cell counting kit-8 (CCK-8) and 5-ethynyl-2′-deoxyuridine (EdU) assays. Cell cycle and apoptosis were analysed by flow cytometry. Oxidative stress was analysed by measuring reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) levels. Results Kisspeptin was downregulated in the ovarian granulosa cells of PCOS rats compared to those of control rats. Kisspeptin overexpression enhanced KGN cell proliferation and inhibited apoptosis. ROS generation was suppressed by kisspeptin, along with decreased levels of MDA and increased levels of the antioxidants GSH, SOD, and CAT. Kisspeptin activates PI3K/AKT and ERK signalling, and inactivation of ERK1/2 suppresses the protective role of kisspeptin in ovarian granulosa cells. Conclusion Kisspeptin improves proliferation and alleviates apoptosis and oxidative stress in ovarian granulosa cells by activating PI3K/AKT and ERK signalling.

Protein Expression and Bioinformatics Study of Granulosa Cells of Polycystic Ovary Syndrome Expressed Under the Influence of DHEA

“…Treatment of CGCs with DHEAS shows altered 2-arachidonoylglycerol biosynthesis, 56 adrenaline and noradrenaline biosynthesis, alpha adrenergic receptor signaling, 34 TGF-beta signaling, 57 Toll receptor signaling, 58 VEGF signaling, 59 and PI3 kinase. 60 Based on these results and previous studies, we propose that MGCs and CGCs behave differently in the presence of DHEAS, possibly activating the pathogenesis of PCOS.…”

Kisspeptin-10 Improves Testicular Redox Status but Does Not Alter the Unfolded Protein Response (UPR) That Is Downregulated by Hypothyroidism in a Rat Model

“…In fact, the reduction in testicular apoptosis appears to be via BCL-2, which showed gene expression almost three times higher in this group. Studies involving kisspeptin and apoptosis are inconsistent, but some have already demonstrated roles in attenuating apoptosis in neurons [62] and in granulosa cells in rat polycystic ovary model [37], which also showed an increase in BCL-2 [37,62], considered an antiapoptotic factor [39].…”

“…In this regard, kisspeptin, which control the hypothalamic release of gonadotropin-releasing hormone (GnRH) [29,30] and has local action in the testes [31,32], has been recognized for its antioxidant effects in models of ovarian and uterine, [33] testicular, [34], cardiac [35] and brain disease in mice [36]. In addition, in vitro overexpression of kisspeptin in human granulosa cells increased proliferation, inhibited apoptosis, suppressed ROS generation, reduced malondialdehyde (MDA) levels, and increased levels of antioxidant factors [37]. These effects observed in several studies justify the use of kisspeptin as a potent antioxidant factor in disease models.…”

Programmed cell death 4: A novel player in the pathogenesis of polycystic ovary syndrome

“…| 5 of 10 aberrant inactivation of various signal transductions, such as Smad1/ 5/8, PI3K/Akt/mTOR, and NF-κB pathways seems to participate in PCOS-induced GC apoptosis. 68,[71][72][73] Furthermore, PCOS might drive GCs into death through apoptosis by downregulating Bcl-2 expression, as well as through ferroptosis by lowering the expression of glutathione peroxidase 4, SLC7A11, and Nrf2. 73 GCs make a substantial contribution to the acquisition of oocyte competence.…”

“…The main suppressor of p53, that is, MDM2, also showed downregulation, leading to a decrease in the ubiquitin‐dependent degradation of p53, and, consequently an increase in its cellular expression and transcriptional activity 70 . The aberrant inactivation of various signal transductions, such as Smad1/5/8, PI3K/Akt/mTOR, and NF‐κB pathways seems to participate in PCOS‐induced GC apoptosis 68,71–73 . Furthermore, PCOS might drive GCs into death through apoptosis by downregulating Bcl‐2 expression, as well as through ferroptosis by lowering the expression of glutathione peroxidase 4, SLC7A11, and Nrf2 73 …”