Gender-specific effects of endogenous testosterone: female alpha-estrogen receptor-deficient C57Bl/6J mice develop glomerulosclerosis

Kidney Int. 2007 Aug;72(4):464-72. doi: 10.1038/sj.ki.5002328. Epub 2007 May 9.

Abstract

Young female mice on a C57Bl/6J (B6) background are considered glomerulosclerosis (GS)-resistant but aging B6 mice develop mild GS. Estrogen deficiency accelerates while estrogen replacement retards GS in young sclerosis-prone oligosyndactyly mutant mice on an ROP background. To explore the effects of sex hormones on glomerular structure and function in the context of gender and genetic background, we studied mice in which the estrogen-receptor (ER) genes alpha- or -beta were deleted (alpha- or betaER knockout (KO)) and crossed into the B6 background. We also studied ovariectomized (Ovx) B6 mice given testosterone. Male and female betaERKO and male alphaERKO mice had no glomerular dysfunction at 9 months of age; however, alphaERKO female mice displayed albuminuria and GS. Ovx prevented glomerular dysfunction in alphaERKO female mice by eliminating endogenous testosterone production while exogenous testosterone induced GS in Ovx B6 mice. Androgen receptor (AR) expression and function was found in microdissected glomeruli and cultured mesangial cells. Testosterone compared to placebo increased both AR expression and TGF-beta1 mRNA levels in glomeruli isolated from female B6 mice. Estrogen deficiency had no deleterious effects on the glomeruli in B6 mice. Our study shows that genetic traits strongly influence the GS-promoting effects of estrogen deficiency while testosterone induces GS in a gender-specific manner.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Albuminuria / genetics
  • Albuminuria / metabolism*
  • Albuminuria / pathology
  • Albuminuria / physiopathology
  • Animals
  • Body Weight
  • Cells, Cultured
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Estradiol / metabolism*
  • Estrogen Receptor alpha / deficiency
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Estrogen Receptor beta / deficiency
  • Estrogen Receptor beta / genetics
  • Estrogen Receptor beta / metabolism*
  • Extracellular Matrix Proteins / metabolism
  • Female
  • Genetic Predisposition to Disease
  • Glomerulosclerosis, Focal Segmental / complications
  • Glomerulosclerosis, Focal Segmental / genetics
  • Glomerulosclerosis, Focal Segmental / metabolism*
  • Glomerulosclerosis, Focal Segmental / pathology
  • Glomerulosclerosis, Focal Segmental / physiopathology
  • Kidney Glomerulus / drug effects
  • Kidney Glomerulus / metabolism*
  • Kidney Glomerulus / pathology
  • Kidney Glomerulus / physiopathology
  • Male
  • Mesangial Cells / metabolism
  • Mesangial Cells / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Organ Size
  • Ovariectomy
  • Promoter Regions, Genetic
  • RNA, Messenger / metabolism
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Sex Factors
  • Signal Transduction
  • Testosterone / metabolism*
  • Testosterone / pharmacology
  • Transfection
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism

Substances

  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Extracellular Matrix Proteins
  • RNA, Messenger
  • Receptors, Androgen
  • Transforming Growth Factor beta1
  • Testosterone
  • Estradiol