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

Abstract

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.

High Circulating Follicle-Stimulating Hormone Level Is a Potential Risk Factor for Renal Dysfunction in Post-Menopausal Women

“…Previous studies have shown that FSH can affect the metabolism of non-gonadal organs such as liver ( 16 , 17 ), adipose tissue ( 33 ), and bone ( 15 , 34 – 36 ), which is supported by our findings. Moreover, FSH receptor is expressed in kidney tissue ( 37 , 38 ) and FSH was shown to promote renal tubulointerstitial fibrosis in aging women via the protein kinase B (AKT)/glycogen synthase kinase (GSK)‐3β/β‐catenin pathway ( 38 ).…”

Genome-wide admixture mapping of eGFR and CKD identify European and African ancestry-of-origin loci in U.S. Hispanics/Latinos

“…In experimental models, FSH caused kidney dysfunction and tubulointerstitial fibrosis, and worsening kidney injury through macrophage recruitment and activation. 25 The NRXN1 gene encodes a single-pass type I membrane protein, which is involved in the central nervous system. Variants in this gene have been implicated in blood pressure, body mass index (BMI) and a range of cognitive traits.…”

Effectiveness Assessment of a Modified Preservation Solution Containing Thyrotropin or Follitropin Based on Biochemical Analysis in Perfundates and Homogenates of Isolated Porcine Kidneys after Static Cold Storage

“…The increased activities of ALT, AST, and LDH in the Biolasol + p-FSH group after 2 h of kidney preservation are noteworthy. This probably indicates increased FSHR expression on renal tubular epithelial cells (RECs), which may result in tubulointerstitial fibrosis [19]. Zhang et al, using an ovariectomized mouse model, found that the administration of recombinant FSH at a dose ranging from 0.15 IU to 0.3 IU increases the protein, creatinine, and urea concentrations in the blood serum of the rodents.…”

“…Zhang et al have confirmed the expression of FSHR on renal tubular epithelial cells (RECs) and on endothelial cells of blood vessels [18]. A strong negative correlation has been demonstrated between eGFR (estimated glomerular filtration rate) and FSH activity in renal function tests [19]. The kidneys play an important role in the excretion of FSH [17].…”