17 beta-estradiol and tamoxifen upregulate estrogen receptor beta expression and control podocyte signaling pathways in a model of type 2 diabetes.
Diabetic nephropathy remains one of the most important causes of end-stage renal disease. This is particularly true for women from racial/ethnic minorities. Although administration of 17beta-estradiol to diabetic animals has been shown to reduce extracellular matrix deposition in glomeruli and mesangial cells, effects on podocytes are lacking. Given that podocyte injury has been implicated as a factor leading to the progression of proteinuria and diabetic nephropathy, we treated db/db mice, a model of type 2 diabetic glomerulosclerosis, with 17beta-estradiol or tamoxifen to determine whether these treatments reduce podocyte injury and decrease glomerulosclerosis. We found that albumin excretion, glomerular volume, and extracellular matrix accumulation were decreased in these mice compared to placebo treatment. Podocytes isolated from all treatment groups were immortalized and these cell lines were found to express the podocyte markers WT-1, nephrin, and the TRPC6 cation channel. Tamoxifen and 17beta-estradiol treatment decreased podocyte transforming growth factor-beta mRNA expression but increased that of the estrogen receptor subtype beta protein. 17beta-estradiol, but not tamoxifen, treatment decreased extracellular-regulated kinase phosphorylation. These data, combined with improved albumin excretion, reduced glomerular size, and decreased matrix accumulation, suggest that both 17beta-estradiol and tamoxifen may protect podocytes against injury and therefore ameliorate diabetic nephropathy.
Catanuto
Paola
P
Study Group and Laboratory on Sex and Gender Differences in Health and Disease, University of Miami, Miller School of Medicine, Miami, Florida, USA; Department of Surgery, University of Miami, Miller School of Medicine, Miami, Florida, USA.
Doublier
Sophie
S
Study Group and Laboratory on Sex and Gender Differences in Health and Disease, University of Miami, Miller School of Medicine, Miami, Florida, USA; Department of Genetics, Biology and Biochemistry, University of Turin, Turin, Italy.
Lupia
Enrico
E
Study Group and Laboratory on Sex and Gender Differences in Health and Disease, University of Miami, Miller School of Medicine, Miami, Florida, USA; Azienda Ospedaliera San Giovanni Battista, Turin, Italy.
Fornoni
Alessia
A
Division of Nephrology, University of Miami, Miller School of Medicine, Miami, Florida, USA.
Berho
Mariana
M
Study Group and Laboratory on Sex and Gender Differences in Health and Disease, University of Miami, Miller School of Medicine, Miami, Florida, USA.
Karl
Michael
M
Study Group and Laboratory on Sex and Gender Differences in Health and Disease, University of Miami, Miller School of Medicine, Miami, Florida, USA; Division of Endocrinology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida, USA.
Striker
Gary E
GE
Department of Surgery, University of Miami, Miller School of Medicine, Miami, Florida, USA.
Xia
Xiaomei
X
Study Group and Laboratory on Sex and Gender Differences in Health and Disease, University of Miami, Miller School of Medicine, Miami, Florida, USA; Department of Surgery, University of Miami, Miller School of Medicine, Miami, Florida, USA.
Elliot
Sharon
S
Study Group and Laboratory on Sex and Gender Differences in Health and Disease, University of Miami, Miller School of Medicine, Miami, Florida, USA; Department of Surgery, University of Miami, Miller School of Medicine, Miami, Florida, USA. Electronic address: selliot@med.miami.edu.
D000818:Animals; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000188:drug therapy; D004958:Estradiol / Q000494:pharmacology*; D047629:Estrogen Receptor beta / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008815:Mice, Inbred Strains; D050199:Podocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020011:Protective Agents; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*
D047629:Estrogen Receptor beta; D020011:Protective Agents; D013629:Tamoxifen; D004958:Estradiol