Testosterone and 17Β-estradiol have opposite effects on podocyte apoptosis that precedes glomerulosclerosis in female estrogen receptor knockout mice

Sophie Doublier, Enrico Lupia, Paola Catanuto, Simone Periera-Simon, Xiaomei Xia, Ken Korach, Mariana Berho, Sharon J. Elliot, Michael Karl

Research output: Contribution to journalArticle

68 Scopus citations

Abstract

Podocyte damage and apoptosis are thought to be important if not essential in the development of glomerulosclerosis. Female estrogen receptor knockout mice develop glomerulosclerosis at 9 months of age due to excessive ovarian testosterone production and secretion. Here, we studied the pathogenesis of glomerulosclerosis in this mouse model to determine whether testosterone and/or 17Β-estradiol directly affect the function and survival of podocytes. Glomerulosclerosis in these mice was associated with the expression of desmin and the loss of nephrin, markers of podocyte damage and apoptosis. Ovariectomy preserved the function and survival of podocytes by eliminating the source of endogenous testosterone production. In contrast, testosterone supplementation induced podocyte apoptosis in ovariectomized wild-type mice. Importantly, podocytes express functional androgen and estrogen receptors, which, upon stimulation by their respective ligands, have opposing effects. Testosterone induced podocyte apoptosis in vitro by androgen receptor activation, but independent of the TGF-Β1 signaling pathway. Pretreatment with 17Β-estradiol prevented testosterone-induced podocyte apoptosis, an estrogen receptor-dependent effect mediated by activation of the ERK signaling pathway, and protected podocytes from TGF-Β1- or TNF-α-induced apoptosis. Thus, podocytes are target cells for testosterone and 17Β-estradiol. These hormones modulate podocyte damage and apoptosis.

Original languageEnglish (US)
Pages (from-to)404-413
Number of pages10
JournalKidney international
Volume79
Issue number4
DOIs
StatePublished - Feb 2011

Keywords

  • apoptosis
  • disease and progression
  • glomerulosclerosis
  • pathophysiology of renal
  • podocyte

ASJC Scopus subject areas

  • Nephrology

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