Testosterone and 17β-estradiol have opposite effects on podocyte apoptosis that precedes glomerulosclerosis in female estrogen receptor knockout mice.
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.
Study Group and Laboratory on Sex and Gender Differences in Health and Disease, Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, Florida, USA.
Sophie
S
Doublier
Enrico
E
Lupia
Paola
P
Catanuto
Simone
S
Periera-Simon
Xiaomei
X
Xia
Ken
K
Korach
Mariana
M
Berho
Sharon J
SJ
Elliot
Michael
M
Karl
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D054337:Cell Dedifferentiation / Q000187:drug effects; D003893:Desmin / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology* / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D047629:Estrogen Receptor beta / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005923:Glomerulosclerosis, Focal Segmental / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010052:Ovariectomy; D050199:Podocytes / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D011944:Receptors, Androgen / Q000378:metabolism; D051906:Smad7 Protein / Q000235:genetics; D013739:Testosterone / Q000494:pharmacology* / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D003893:Desmin; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008565:Membrane Proteins; D011944:Receptors, Androgen; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; C113267:nephrin; D013739:Testosterone; D004958:Estradiol