Research Paper Volume 11, Issue 21 pp 9500—9529

ER-depletion lowering the 'hypothalamus-uterus-kidney' axis functions by perturbing the renal ERβ/Ptgds signalling pathway

Yan-Ru Liu1, *, , Zhi-Shu Tang1, *, , Jin-Ao Duan2, , Lin Chen1, , Jing Sun1, , Rui Zhou1, , Zhong-Xing Song1, , Xin-Bo Shi1, , Hui-Yuan Zhu3, ,

  • 1 Shaanxi Province Key Laboratory of New Drugs and Chinese Medicine Foundation Research, Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Shaanxi University of Chinese Medicine, Xianyang 712083, P.R. China
  • 2 Key Laboratory for High Technology Research of TCM Formulae and Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China
  • 3 Shaanxi University of Chinese Medicine, Xianyang 712083, P.R. China
* Equal contribution

Received: June 6, 2019       Accepted: October 26, 2019       Published: November 10, 2019
How to Cite

Copyright © 2019 Liu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Researchers have long assumed that systematic estrogen fading might contribute to the sustained progression of menopausal degenerate syndromes, although definitive evidence has not been presented. Whether such findings represent a causal contribution or are the result of opportunistic messengers sent from the reproductive system to the brain is also a vital question. We constructed a multiscale network of the ovariectomy (OVX) induced estrogen receptors depletion (ER-depletion) model and integrated targeted proteomic, targeted lipidomic, cytochemical, and histopathological data across three tissues from the ovariectomy rodent model. We found that compared to control rats, OVX rats showed increased renal and uterine prostaglandin D2 synthase (Ptgds) expression and decreased hypothalamic Ptgds expression, abnormal Ptgds metabolites, the degenerate renal function profiles and decreased cognitive ability (learning and memory) in Morris water maze test. Importantly, we observed a regulatory relationship among ER (particularly ERβ), the degree of the pathological phenotype, learning behavior test and the ‘hypothalamus-uterus-kidney (HUK) axis functions. Collectively, this study elucidates that ER depletion promoted HUK aging is mostly attributed to a renal ERβ/Ptgds signalling imbalance.


ER: estrogen receptors; OVX: ovariectomy; IPA: Ingenuity pathway analysis; Ptgds: prostaglandin D2 synthase; HUK axis: hypothalamus-uterus-kidney axis; CKD: chronic kidney disease; E2: oestradiol; IHC: immunohistochemistry; WB: Western blot; qPCR: quantitative PCR; PCA: principal component analysis; PLS-DA: partial least squares-discriminant analysis; AUC: area under the curve; UPLC-TOF/MS: ultra-high-performance liquid chromatography-quadrupole time-of-flight MS; IDA: information-dependent data; Itraq: isobaric tag for relative and absolute quantitation; GO: Gene Ontology; MRM: multiple reaction monitoring; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; KEGG: Kyoto Encyclopedia of Genes and Genomes.