MON-226 FSH Promotes Renal Tubulointerstitial Fibrosis Via AKT/GSK-3beta/beta-catenin Pathway

Background: Estrogen withdraw in postmenopausal women undoubtedly contributes to the progression of chronic kidney disease (CKD). However, the effect of high circulating follicle-stimulating hormone (FSH) level on renal dysfunction remains unknown. We aimed to investigate whether FSH participates in renal development during postmenopausal period. Methods: 3055 postmenopausal blood samples were collected and tested. The effects of FSH on renal function were evaluated in cell and mice model of high FSH level. Results: Based on clinical data analyses, we found that there was a strong negative correlation between eGFR and FSH levels (P<0.001), especially independent of LH, testosterone and estradiol. Functional FSHR was detected in renal tubular epithelial cell. In vivo, high FSH promoted a phenotype of tubulointerstitial fibrosis, characterized by increase in 24h uric protein, serum Cr, serum BUN, as well as ECM deposition. Similar results obtained from cultured HK-2 cells, FSH increased the transcriptional and protein expressions of profibrotic mediators (Collagen IV, Fibronectin and PAI-1). Furthermore, this fibrosis promotion by FSH was through activation of AKT/GSK-3β/β-catenin pathway that could be attenuated by silence of FSHR by siRNA or LY294002. Besides, FSH-stimulated HK-2 secreted chemokines, such as IL-8, promoted macrophages migration to exacerbate tubulointerstitial fibrosis. Conclusion: Functional FSHR was expressed in renal tubular epithelial cells and FSH aggravated renal dysfunction and tubulointerstitial fibrosis via FSHR-mediated AKT/GSK-3β/β-catenin pathway. Our results revealed a previously unknown contribution of FSH to postmenopausal kidney injury.