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17beta -Estradiol modulates mechanical strain-induced MAPK activation in mesangial cells
Joan Krepinsky1, Alistair J Ingram, Leighton James
1Department of Medicine, University of Toronto, Toronto, Ontario M5G 2C4, Canada. joan.krepinsky@utoronto.ca
The Journal of Biological Chemistry
|January 5, 2002
Summary
Female gender protects against kidney disease by reducing mechanical strain on glomerular cells. Estradiol, a key female hormone, inhibits stress-activated pathways, potentially through MKP-1, offering insights into gender-based renal protection.
Area of Science:
- Nephrology
- Endocrinology
- Molecular Biology
- Cellular Signaling
Background:
- Female gender is associated with better outcomes in various kidney diseases.
- The underlying mechanisms for this gender-based protection remain incompletely understood.
- Mechanical stress on glomerular cells contributes to kidney injury, particularly in conditions like remnant kidney disease.
Purpose of the Study:
- To investigate the role of 17beta-estradiol in modulating mechanical strain-induced signaling in glomerular mesangial cells (MC).
- To elucidate the specific signaling pathways affected by 17beta-estradiol under mechanical stress.
- To determine if estrogen receptor signaling mediates the effects of 17beta-estradiol on MCs.
Main Methods:
- Cultured rat glomerular mesangial cells (MC) were subjected to mechanical strain.
- Cells were pretreated with 17beta-estradiol and then exposed to mechanical strain.
- Activation of p44/42 mitogen-activated protein kinase (MAPK) and stress-activated protein kinase (SAPK) was assessed via Western blotting.
- Nuclear translocation of kinases and activator protein-1 (AP-1) binding were analyzed.
- The role of estrogen receptors was confirmed using an estrogen receptor antagonist (ICI-182,780).
Main Results:
- Mechanical strain significantly increased p44/42 MAPK and SAPK activation in MCs.
- 17beta-estradiol dose-dependently inhibited mechanical strain-induced activation and nuclear translocation of p44/42 MAPK and SAPK.
- 17beta-estradiol attenuated mechanical strain-induced nuclear protein binding to AP-1.
- The inhibitory effects of 17beta-estradiol were dependent on intracellular estrogen receptor signaling and were associated with increased expression of the dual specificity phosphatase MKP-1.
Conclusions:
- 17beta-estradiol attenuates mechanical strain-induced activation of MAPK and SAPK pathways in glomerular mesangial cells.
- This protective effect is mediated through intracellular estrogen receptor signaling.
- Increased expression of MKP-1 may contribute to the inhibition of stress-induced kinase activation, offering a molecular basis for gender-based protection in kidney disease.