Numerous studies have established a role for
mineralocorticoids in the development of renal
fibrosis. Originally, the research focus for
mineralocorticoid-induced
fibrosis was on the collecting duct, where 'classical'
mineralocorticoid receptors (MRs) involved with
electrolyte transport are present. Epithelial cells in this segment can, under selected circumstances, also respond to MR activation by initiating pro-fibrotic pathways. More recently, 'non-classical' MRs have been described in kidney cells not associated with
electrolyte transport, including mesangial cells and podocytes within the glomerulus. Activation of MRs in these cells appears to lead to glomerular
sclerosis. Mechanistically,
aldosterone induces excess production of
reactive oxygen species (ROS) and oxidative stress in glomerular cells through activation of
NADPH oxidase. In mesangial cells,
aldosterone also has pro-apoptotic, mitogenic and pro-fibrogenic effects, all of which potentially promote active remodelling and expansion of the mesangium. Although
mitochondrial dysfunction seems to mediate the
aldosterone-induced mesangial apoptosis, the ROS dependent epithelial
growth factor receptor (EGFR) transactivation is probably responsible for
aldosterone-induced mesangial mitosis and proliferation. In podocytes,
mitochondrial dysfunction elicited by oxidative stress is an early event associated with
aldosterone-induced podocyte injury. Both the
p38 MAPK (
p38 mitogen-activated protein kinase) signalling and the redox-sensitive
glycogen synthase kinase (GSK)3β pathways are centrally implicated in
aldosterone-induced podocyte death.
Aldosterone-induced GSK3β over-activity could potentially cause hyperphosphorylation and over-activation of putative GSK3β substrates, including structural components of the mitochondrial permeability transition (MPT) pore, all of which lead to cell injury and death. Clinically,
proteinuria significantly decreases when
aldosterone inhibitors are included in the treatment of many glomerular diseases further supporting the view that
mineralocorticoids are important players in glomerular pathology.