17β-estradiol modulates mechanical strain-induced MAPK activation in mesangial cells

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 17β-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 17β-estradiol (10^-8 to 10^-11 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 17β-estradiol. The inhibitory effects of 17β-estradiol were not reproduced by the cell- impermeable estrogen, BSA/17β-estradiol, nor did preincubation with 17β-estradiol lead to actin cytoskeleton disassembly or impaired stress fiber formation. However, 17β-estradiol did increase base-line levels of the dual specificity phosphatase MKP-1. The inhibitory effects of 17β-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 17β-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 17β-estradiol on MKP-1 expression. Together, these findings add insight into the protective effect of gender on renal disease progression.