Abstract
Evidence suggests that aldosterone (ALD) is involved in glomerular damage; however, it is rarely known whether ALD exerts a direct injurious effect on mesangial cells (MC). The objectives of this study were to determine the relationship between ALD and apoptosis, and investigate the cell signalling pathway by which ALD induces apoptosis. Rat MC were treated with ALD (10-8, 10-7 or 10-6 M) for 24 h. In some experiments, MC were pretreated with 10-7 M spironolactone or 10-2 M LiCl for 1 h. Apoptosis was quantified using Annexin V-propidium iodide staining and flow cytometry, and caspase 3 activity was analysed. Gene and protein expression were quantified using quantitative real-time PCR and Western blotting, respectively. ALD directly induced apoptosis in MC in a caspase dependent manner. More importantly, Wnt signalling was involved in ALD-induced cell apoptosis. ALD suppressed the Wnt signalling pathway in MC, leading to downregulation of Wnt4 and Wnt5a mRNA expression, increased GSK-3β protein expression and reduced β-catenin protein expression. A competitive antagonist of ALD, spironolactone (SPI), attenuated the ability of ALD to inhibit Wnt signalling. The Wnt signalling agonist, LiCl, inhibited ALD-induced apoptosis. This study suggests that ALD may directly induce apoptosis in MC via the Wnt signalling pathway. Modulation of Wnt signal transduction may be beneficial for enhancing mesangial cell survival in renal injury. Key words: Aldosterone, apoptosis, β-catenin, GSK-3β, mesangial cells.
Highlights
Aldosterone (ALD) is an important mediator of the reninangiotensin-ALD system (RAAS) and plays a pivotal role in the regulation of salt and extracellular fluid metabolism (Chen et al, 2009)
Plasma and tissue ALD levels are elevated in diabetic and other progressive nephropathies (Boldyreff and Wehling, 2003), and elevated plasma ALD may contribute to the progression of renal disease via direct actions on tubulointerstitial fibroblasts, glomerular mesangial cells (MC) and podocytes (Brilla et al, 1993; Chrysostomou and Becker, 2001; Lai et al, 2006)
Molecular mechanisms including reactive oxygen species (ROS), MAPKs and Rho-kinase signalling may be involved in ALD-induced renal injury (Huang et al, 2009; Sun et al, 2006; Toyonaga et al, 2011) to our knowledge, it is not known whether ALD can induce apoptosis via the Wnt signalling pathway
Summary
Aldosterone (ALD) is an important mediator of the reninangiotensin-ALD system (RAAS) and plays a pivotal role in the regulation of salt and extracellular fluid metabolism (Chen et al, 2009). Accumulating evidence suggests that ALD is a key factor which mediates renal injury (Ando et al, 2010; Diah et al, 2008; Fan et al, 2011). Several experimental reports suggest that ALD, in addition to exerting hemodynamic effects, may directly contribute to the occurrence of mesangial cell (MC) apoptosis (Mathew et al, 2008).The Wnt signalling pathway is essential during development and acts as a regulator of embryonic cell patterning, proliferation, differentiation, cell adhesion, cell survival and apoptosis (Bridgewater et al, 2011; Merkel et al, 2007; Vinas et al, 2010; Zeilstra et al, 2011). Lin et al (2006) suggested that Wnt signalling modulates the survival of high glucose-stressed MC
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