Aldosterone activates the oncogenic signals ERK1/2 and STAT3 via redox-regulated mechanisms

Area of Science:

• Endocrinology
• Oncology
• Molecular Biology

Background:

• Hypertension is linked to increased kidney cancer risk, particularly in patients with high aldosterone (Ald) levels.
• Aldosterone has demonstrated genotoxic effects in kidney cells and hypertensive rats.
• The potential oncogenic mechanisms of excess aldosterone exposure require further investigation.

Purpose of the Study:

• To investigate if oxidative stress-mediated activation of the ERK1/2 pathway and its downstream target STAT3 are involved in aldosterone's potential oncogenic capability.
• To explore the effects of excess aldosterone on cell proliferation and apoptosis in vitro and in vivo.

Main Methods:

• Aldosterone's effects were studied in LLC-PK1 cells and in rats with aldosterone-induced hypertension.
• Key signaling proteins (cRaf, MEK1/2, ERK1/2, MSK1, p90RSK, STAT3) were analyzed for phosphorylation.
• The role of the mineralocorticoid receptor and cellular oxidants (NADPH oxidase, NO synthase) was assessed.
• A MEK inhibitor (U0126) was used to confirm pathway involvement.

Main Results:

• Excess aldosterone induced phosphorylation of cRaf, MEK1/2, and ERK1/2 in kidney cells and rat kidneys.
• ERK1/2 activation led to increased phosphorylation of MSK1, p90RSK, and STAT3.
• Aldosterone-mediated ERK1/2 and STAT3 activation was dependent on the mineralocorticoid receptor and cellular oxidants.
• Aldosterone increased cell proliferation and decreased apoptosis in kidney cells and rat kidneys.

Conclusions:

• Oxidant-mediated activation of the ERK1/2/STAT3 pathway by high aldosterone levels promotes cell survival and proliferation.
• These aldosterone-induced events may contribute to kidney cell transformation and cancer initiation in hyperaldosteronism.
• The findings elucidate a potential molecular mechanism linking aldosterone excess to kidney cancer development.