2-Hydroxyestradiol slows progression of experimental polycystic kidney disease

Am J Physiol Renal Physiol. 2012 Mar 1;302(5):F636-45. doi: 10.1152/ajprenal.00265.2011. Epub 2011 Dec 7.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Methoxyestradiol
  • Animals
  • Apoptosis / drug effects
  • Cell Proliferation / drug effects
  • Disease Progression
  • Estradiol / analogs & derivatives*
  • Estradiol / pharmacology
  • Estradiol / therapeutic use
  • Kidney / drug effects*
  • Kidney / metabolism
  • Kidney / pathology
  • Male
  • Orchiectomy
  • Polycystic Kidney Diseases / drug therapy*
  • Polycystic Kidney Diseases / metabolism
  • Polycystic Kidney Diseases / pathology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / metabolism
  • Treatment Outcome

Substances

  • Estradiol
  • 2-Methoxyestradiol
  • 2-hydroxyestradiol
  • TOR Serine-Threonine Kinases
  • mTOR protein, rat
  • Proto-Oncogene Proteins c-akt