Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Institute and Department of Gynecology and Obstetrics, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Zhejiang, China.
Aging Cell. 2019 Oct;18(5):e12997. doi: 10.1111/acel.12997. Epub 2019 Jun 26.
Estrogen withdrawal in aging women contributes to the progression of chronic kidney disease (CKD). However, the effect of high circulating follicle-stimulating hormone (FSH) levels on renal dysfunction remains unknown. In this study, blood samples from 3,055 postmenopausal women were collected and tested, which showed that there was a strong negative correlation between eGFR and FSH levels (p < 0.001), independent of LH, testosterone, and estradiol. Functional FSHR was detected in renal tubular epithelial cells. In vivo, high circulating FSH levels promoted a phenotype of tubulointerstitial fibrosis, characterized by increases in 24-hr urine protein/creatinine ratio, serum Cr, serum BUN, and ECM deposition. Similar results obtained from cultured HK-2 cells showed that FSH increased the transcriptional and protein expression of profibrotic mediators (collagen IV, fibronectin, and PAI-1). This promotion of fibrosis by FSH occurred through the activation of AKT/GSK-3β/β-catenin pathway, which could be attenuated by silencing FSHR by siRNA or by LY294002 or MK2206. In addition, FSH-stimulated HK-2 cells secreted IL-8, which promoted macrophage migration to exacerbate tubulointerstitial fibrosis. These results revealed a previously unknown effect of FSH on kidney injury, which may offer a critical insight into the development of CKD in aging postmenopausal women.
绝经后女性的雌激素撤退会导致慢性肾脏病（CKD）的进展。然而，高循环卵泡刺激素（FSH）水平对肾功能障碍的影响尚不清楚。在这项研究中，收集并检测了 3055 名绝经后妇女的血样，结果表明 eGFR 与 FSH 水平之间存在强烈的负相关（p<0.001），与 LH、睾酮和雌二醇无关。在肾小管上皮细胞中检测到功能性 FSHR。在体内，高循环 FSH 水平促进了肾小管间质纤维化的表型，表现为 24 小时尿蛋白/肌酐比、血清 Cr、血清 BUN 和 ECM 沉积增加。从培养的 HK-2 细胞中获得的类似结果表明，FSH 增加了促纤维化介质（IV 型胶原、纤维连接蛋白和 PAI-1）的转录和蛋白表达。FSH 对纤维化的促进作用是通过激活 AKT/GSK-3β/β-catenin 通路实现的，这可以通过 siRNA 或 LY294002 或 MK2206 沉默 FSHR 来减弱。此外，FSH 刺激的 HK-2 细胞分泌 IL-8，促进巨噬细胞迁移，加重肾小管间质纤维化。这些结果揭示了 FSH 对肾脏损伤的一个以前未知的作用，这可能为绝经后老年妇女 CKD 的发展提供了一个关键的见解。
