<p><b><i>Background/Aims:</i></b> The mineralocorticoid hormone,
aldosterone, has pro-fibrotic properties which can cause kidney damage.
The severity of kidney interstitial fibrosis is dependent on the
accumulation of fibroblasts, which result largely from local
proliferation; however, it is unknown whether aldosterone stimulates
kidney fibroblast proliferation. Therefore, we examined the effects of
aldosterone on the proliferation of cultured kidney fibroblasts. <b><i>Methods:</i></b> Uptake of <sup>3</sup>H-thymidine
and cell number quantitation were used to determine the proliferative
effects of aldosterone on a rat kidney fibroblast cell line (NRK49F
cells) and interstitial fibroblasts extracted from mouse kidneys after
unilateral ureter obstruction. The role of different mitogenic
signalling pathways in aldosterone-induced proliferation was assessed
using specific inhibitors of receptors and kinases. <b><i>Results:</i></b>
Physiological levels of aldosterone induced a doubling of proliferation
of kidney fibroblasts (p < 0.0001), which was inhibited by
pre-treatment with the mineralocorticoid receptor antagonist,
eplerenone. Aldosterone-induced fibroblast proliferation was dependent
upon the kinase activity of growth factor receptors [platelet-derived
growth factor receptor (PDGFR) and epidermal growth factor receptor].
Notably, PDGF ligands were not involved in aldosterone-induced PDGFR
activation, indicating receptor transactivation. Aldosterone-induced
fibroblast proliferation also required signalling via PI3K, JNK and ERK
pathways, but not via the transforming growth factor-β<sub>1</sub> receptor. <b><i>Conclusion:</i></b>
Aldosterone ligation of the mineralocorticoid receptor in kidney
fibroblasts results in rapid activation of growth factor receptors and
induction of PI3K/MAPK signalling, which stimulates proliferation. This
suggests that increased levels of aldosterone during disease may promote
the severity of kidney fibrosis by inducing fibroblast proliferation.</p
