Rosiglitazone suppresses FSH and IGF-1 induced downstream PI3K/Akt pathway mediated granulosa cell function involving PPARg and PTEN: Potential targets of fertility regulation

I. Sharma, Dheer Singh
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引用次数: 1

Abstract

Nuclear receptor peroxisome proliferative activated receptor gamma (PPARg) is a prominent targeted molecule in ovarian syndrome. Rosiglitazone, a potent drug administered during Polycystic ovarian syndrome (PCOS), executes its effects through this receptor. However, the exact mechanism through which Rosiglitazone induces PPARg and mediates its action in ovary is not well documented. In the present study, we delineated the signaling pathway for Rosiglitazone action in granulosa cell functioning by using buffalo granulosa cell model. Experiments were performed in serum free primary buffalo granulosa cell culture when cells were follicle stimulating hormone (FSH) responsive with pre-ovulatory phenotype. The cells were incubated with Rosiglitazone alone or in combination with FSH (25 ng/ml) and IGF-1(50 ng/ml). Results showed that Rosiglitazone (25 µM) inhibited FSH and insulin like growth factor-1 (IGF-1) induced granulosa cell proliferation, aromatase, GATA-4, IGF-1 mRNA and oestradiol-17β production. Western blot analysis of total cell lysates revealed that Rosiglitazone intervene with the FSH and IGF-1 signaling by decreasing p-Akt. In addition, Rosiglitazone was found to up-regulate PPAR g and (PTEN) in granulosa cells. PPARg antagonist (GW9662) had no effect on p-Akt level, as well as on steroidogenesis. PTEN inhibitor bpV(pic) revived Akt phosphorylation to the level of control. In conclusion, the present study demonstrated that Rosiglitazone attenuated FSH and IGF-1 induced downstream PI3K/Akt pathway mediated granulosa cell function ( proliferation and steroidogenesis) involving PPARg and PTEN . The elucidated signaling pathway and participating molecules, PPARg and PTEN, could be potential targets while developing novel molecules in PCOS management and fertility regulation
罗格列酮抑制FSH和IGF-1诱导的下游PI3K/Akt通路介导的颗粒细胞功能,包括PPARg和PTEN:生育调节的潜在靶点
核受体过氧化物酶体增殖性激活受体γ (PPARg)是卵巢综合征的重要靶向分子。罗格列酮是一种治疗多囊卵巢综合征(PCOS)的有效药物,通过该受体发挥作用。然而,罗格列酮诱导PPARg并介导其在卵巢中的作用的确切机制尚不清楚。在本研究中,我们通过水牛颗粒细胞模型描绘了罗格列酮作用在颗粒细胞功能中的信号通路。实验在无血清原代水牛颗粒细胞培养中进行,当细胞对促卵泡激素(FSH)具有排卵前表型反应时。罗格列酮单独或联合FSH (25 ng/ml)和IGF-1(50 ng/ml)孵育细胞。结果表明,罗格列酮(25µM)抑制FSH和胰岛素样生长因子-1 (IGF-1)诱导的颗粒细胞增殖、芳香化酶、gta -4、IGF-1 mRNA和雌二醇-17β的产生。Western blot分析总细胞裂解物显示罗格列酮通过降低p-Akt干预FSH和IGF-1信号。罗格列酮上调颗粒细胞PPAR g和(PTEN)水平。PPARg拮抗剂(GW9662)对p-Akt水平和甾体生成没有影响。PTEN抑制剂bpV(pic)使Akt磷酸化恢复到控制水平。总之,本研究表明,罗格列酮减弱FSH和IGF-1诱导下游PI3K/Akt通路介导的颗粒细胞功能(增殖和甾体生成)涉及PPARg和PTEN。PPARg和PTEN等信号通路及其参与分子可能成为PCOS管理和生育调控新分子的潜在靶点
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