title: Diabetic nephropathy is associated with decreased circulating estradiol levels and imbalance in the expression of renal estrogen receptors.
abstract: BACKGROUND
  The incidence of cardiovascular and renal disease is lower in premenopausal women than in aged-matched men. However, in the setting of diabetes mellitus (DM), this "female advantage" no longer exists: the incidence and progression of DM and its associated end-organ complications are equal in men and women, regardless of age. We have recently reported that estrogen supplementation attenuates the progression of diabetic nephropathy, suggesting that lack of estrogen may nullify female sex as a protective factor against DM.
  
  
  OBJECTIVE
  This study examined circulating levels of estradiol in DM and expression of estrogen receptor subtypes (ERa and ERP) in the nondiabetic (ND) and diabetic (D) kidney.
  
  
  METHODS
  : The study was performed in ND and streptozotocin-induced D Sprague-Dawley rats after 2 weeks (male and female) and 12 weeks (female) of DM. The animals (N = 8/group) were kept either intact, ovariectomized (OVX), or OVX with 17beta-estradiol (E(2)) supplementation (OVX + E(2), 5 mug/kg/d). Plasma estradiol levels were measured by enzyme-linked immunosorbent assay, and expression of renal ERalpha and ERbeta was measured by immunohistochemistry and Western blot analysis.
  
  
  RESULTS
  DM was associated with reduced circulating estradiol levels (ND: mean [SEM] 37.1 [7.2]; D: 24.5 [9.3] pg/mL; P < 0.05). The diabetic kidney exhibited increased expression of ERalpha protein (ND: 0.82 [0.06]; D: 1.15 [0.09] arbitrary units; P < 0.05), but no differences in ERP were observed. This resulted in an overall increase in the ratio of ERalpha/ERbeta protein expression in the diabetic kidney. No differences in the expression of ERa were observed in either females or males with similar glycemic levels after 2 weeks of DM.
  
  
  CONCLUSIONS
  Reduced circulating levels of estradiol and imbalance in the expression of estrogen receptor subtypes in the diabetic kidney may explain why female sex is no longer a protective factor in the setting of DM. Thus, estradiol supplementation may be an effective regimen in attenuating the onset and progression of diabetic renal complications.
authors.affiliation: Department of Medicine, Georgetown University Medical Center, Washington, DC 20057, USA. cm255@georgetown.edu
authors.forename: Corinne C
authors.initials: CC
authors.lastname: Wells
authors.forename: Shahla
authors.initials: S
authors.lastname: Riazi
authors.forename: Richard W
authors.initials: RW
authors.lastname: Mankhey
authors.forename: Faizah
authors.initials: F
authors.lastname: Bhatti
authors.forename: Carolyn
authors.initials: C
authors.lastname: Ecelbarger
authors.forename: Christine
authors.initials: C
authors.lastname: Maric
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000097:blood* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000097:blood* / Q000503:physiopathology; D018450:Disease Progression; D004958:Estradiol / Q000097:blood; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000378:metabolism*; D005260:Female; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004958:Estradiol