Follicle‐stimulating hormone promotes renal tubulointerstitial fibrosis in aging women via the AKT/GSK‐3β/β‐catenin pathway

: 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.