A thorough understanding of epigenetics regulatory mechanisms of premature ovarian failure (POF) is still lacking. Here, we found that cyclophosphamide induced significantly decrease in alpha-Klotho (Kl) expression in mouse ovarian granulosa cells (mOGCs), suggesting that cyclophosphamide inhibited Kl expression. Cyclophosphamide also significantly accelerated ageing and led to a decline in the pregnancy rate of C. elegans. We subsequently noted that the pathological condition exhibited by Kl(-/-) mice was similar to that observed in cyclophosphamide-induced POF mice. Furthermore, the mOGCs in both types of mice showed significant signs of oxidative stress damage, including decreased SOD and ATP, increased ROS levels. Detailed analyses revealed that the decreased Kl expression led to the reduced expression of autophagy-related proteins in mOGCs, which resulted in decreased autophagy activity. Finally, we found that cyclophosphamide attenuated the autophagy function of mOGCs via upregulating microRNA-15b expression, which silenced the endogenous Kl mRNA expression and stimulated the activity of the downstream TGF beta 1/Smad pathway. Therefore, we demonstrated that Kl was one of the key inhibitory factors in the development of POF. It elucidated the underlying epigenetic regulatory mechanism, whereby cyclophosphamide-dependent microRNA-15b inhibited Kl expression, leading to the reduced ability of mOGCs to induce autophagy and ROS scavenging, ultimately causing POF.
[1]Shanghai Univ Tradit Chinese Med, Shanghai Geriatr Inst Chinese Med, Shanghai 200031, Peoples R China.
[2]Shanghai Jiao Tong Univ, Shanghai Gen Hosp, Sch Med, Dept Ophthalmol, Shanghai 200080, Peoples R China.
[3]Shanghai Topbiox Co Ltd, Shanghai 200031, Peoples R China.
[4]Fudan Univ, Huashan Hosp, Dept Nephrol, Shanghai 200040, Peoples R China.
(8.0+极速模式)