title: 17beta -Estradiol modulates mechanical strain-induced MAPK activation in mesangial cells.
abstract: Gender is an important determinant of clinical outcome across a broad spectrum of kidney diseases, but the mechanism(s) responsible for the protective effect of female gender have not been fully elucidated. Remnant kidney glomerular injury is limited in female rats compared with male rats despite similar elevations in glomerular capillary pressure. In vitro, mechanical strain leads to the activation of p44/42 mitogen-activated kinase (p44/42 MAPK) and Jun N-terminal kinase/stress-activated protein kinase (SAPK) in glomerular mesangial cells (MC). Accordingly, we studied the effect of 17beta-estradiol on mechanical strain-induced signal transduction in MC. Exposure of MC to mechanical strain increased p44/42 MAPK activation (3-fold) and SAPK activation (2.5-fold), and kinase activation was inhibited by pretreatment with 17beta-estradiol (10(minus sign8) to 10(minus sign11) m) for 24 h in a dose-dependent manner. Mechanical strain-induced nuclear translocation of p44/42 MAPK and SAPK and nuclear protein binding to AP-1 were also attenuated by 17beta-estradiol. The inhibitory effects of 17beta-estradiol were not reproduced by the cell-impermeable estrogen, BSA/17beta-estradiol, nor did preincubation with 17beta-estradiol lead to actin cytoskeleton disassembly or impaired stress fiber formation. However, 17beta-estradiol did increase base-line levels of the dual specificity phosphatase MKP-1. The inhibitory effects of 17beta-estradiol on p44/42 MAPK activation and SAPK activation, translocation, and AP-1 binding were all abrogated by the estrogen receptor antagonist, ICI-182,780. We conclude that attenuation of mechanical strain-induced MAPK activation by 17beta-estradiol is dependent on intracellular estrogen receptor. The attenuation of stretch-induced kinase activation may be due, at least in part, to an effect of 17beta-estradiol on MKP-1 expression. Together, these findings add insight into the protective effect of gender on renal disease progression.
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario M5G 2C4, Canada. joan.krepinsky@utoronto.ca
authors.forename: Joan
authors.initials: J
authors.lastname: Krepinsky
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Ingram
authors.forename: Leighton
authors.initials: L
authors.lastname: James
authors.forename: Hao
authors.initials: H
authors.lastname: Ly
authors.forename: Kerri
authors.initials: K
authors.lastname: Thai
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Cattran
authors.forename: Judith A
authors.initials: JA
authors.lastname: Miller
authors.forename: James W
authors.initials: JW
authors.lastname: Scholey
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D018797:Cell Cycle Proteins; D003599:Cytoskeleton / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D054638:Dual Specificity Phosphatase 1; D004789:Enzyme Activation; D004958:Estradiol / Q000494:pharmacology*; D016762:Genes, fos; D005920:Glomerular Mesangium / Q000201:enzymology*; D017874:Immediate-Early Proteins / Q000096:biosynthesis; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013314:Stress, Mechanical; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D018808:Transcription Factor AP-1; D004958:Estradiol; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517021:Dusp1 protein, rat; D017027:Protein Tyrosine Phosphatases