Aldosterone induces kidney fibroblast proliferation via activation of growth factor receptors and PI3K/MAPK signalling.
OBJECTIVE
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.


METHODS
Uptake of (3)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.


RESULTS
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-β1 receptor.


CONCLUSIONS
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.
Department of Nephrology, Monash Medical Centre, Clayton, Vic., Australia.
L L
LL
Huang
D J
DJ
Nikolic-Paterson
F Y
FY
Ma
G H
GH
Tesch
D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects; D007668:Kidney / Q000166:cytology* / Q000187:drug effects* / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051381:Rats; D017978:Receptors, Growth Factor / Q000378:metabolism*; D018161:Receptors, Mineralocorticoid / Q000378:metabolism
D000451:Mineralocorticoid Receptor Antagonists; D017978:Receptors, Growth Factor; D018161:Receptors, Mineralocorticoid; D000450:Aldosterone; D019869:Phosphatidylinositol 3-Kinases