title: 2-Hydroxyestradiol slows progression of experimental polycystic kidney disease.
abstract: Male gender is a risk factor for progression of polycystic kidney disease (PKD). 17β-Estradiol (E2) protects experimentally, but clinical use is limited by adverse effects. Novel E2 metabolites provide many benefits of E2 without stimulating the estrogen receptor, and thus may be safer. We hypothesized that E2 metabolites are protective in a model of PKD. Studies were performed in male control Han:SPRD rats, and in cystic males treated with orchiectomy, 2-methoxyestradiol, 2-hydroxyestradiol (2-OHE), or vehicle, from age 3 to 12 wk. Cystic rats exhibited renal functional impairment (∼50% decrease in glomerular filtration and renal plasma flow rates, P < 0.05) and substantial cyst development (20.5 ± 2.0% of cortex area). 2-OHE was the most effective in limiting cysts (6.0 ± 0.7% of cortex area, P < 0.05 vs. vehicle-treated cystic rats) and preserving function, in association with suppression of proliferation, apoptosis, and angiogenesis markers. Downregulation of p21 expression and increased expression of Akt, the mammalian target of rapamycin (mTOR), and some of its downstream effectors were significantly reversed by 2-OHE. Thus, 2-OHE limits disease progression in a cystic rodent model. Mechanisms include reduced renal cell proliferation, apoptosis, and angiogenesis. These effects may be mediated, at least in part, by preservation of p21 and suppression of Akt and mTOR. Estradiol metabolites may represent a novel, safe intervention to slow progression of PKD.
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Oregon Health & Science University, Portland, OR 97239, USA. anderssh@ohsu.edu
authors.forename: Sharon
authors.initials: S
authors.lastname: Anderson
authors.forename: Terry T
authors.initials: TT
authors.lastname: Oyama
authors.forename: Jessie N
authors.initials: JN
authors.lastname: Lindsley
authors.forename: William E
authors.initials: WE
authors.lastname: Schutzer
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Beard
authors.forename: Vincent H
authors.initials: VH
authors.lastname: Gattone
authors.forename: Radko
authors.initials: R
authors.lastname: Komers
mesh_terms: D000077584:2-Methoxyestradiol; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009919:Orchiectomy; D007690:Polycystic Kidney Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D004958:Estradiol; D000077584:2-Methoxyestradiol; C001390:2-hydroxyestradiol; C546845:mTOR protein, rat; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases