Cross-talk between mineralocorticoid receptor/angiotensin II type 1 receptor and mitogen-activated protein kinase pathways underlies aldosterone-induced atrial fibrotic responses in HL-1 cardiomyocytes

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Nongenomic effects via the mineralocorticoid receptor

“…For angII receptor I (AT1), a complex interaction with aldosterone/MR signaling on different levels is reported in literature and spironolactone, for example, can inhibit angII-mediated pathological effects by improving cardiac and vascular changes, including fibrosis, hypertrophy and oxidative stress in rats (Ullian et al 1992, Fiebeler et al 2001, Virdis et al 2002, Neves et al 2003. Besides a genomic component whereby aldosterone regulates ACE 234:1 (and thereby angII synthesis), MR and AT1 expression in the cardiovascular system, MR and AT1 signaling cascades also interact on a nongenomic level (Zennaro et al 1996, Sugiyama et al 2005, Hirono et al 2007, Tsai et al 2013). In VSMCs this was shown by demonstrating a synergistic effect of angII and aldosterone on ERK1/2 phosphorylation that results in cell proliferation, migration and cell senescence (Mazak et al 2004, Min et al 2005.…”

Mineralocorticoid regulation of cell function: the role of rapid signalling and gene transcription pathways

“…The relationship among aldosterone, angiotensin II, MR and AGTR1 serves to mutually enhance the signalling of each individual ligand-receptor system. Aldosterone is able to upregulate the expression of both MR and AGTR1 (Schiffrin et al 1985, Zennaro et al 1996, Tsai et al 2013. In cardiomyocytes, aldosterone control of MR expression is dependent on MR coupled to AGTR1 signalling and downstream ERK and JNK activation, whereas AGTR1 expression is regulated by MR-independent transactivation of AGTR1 signalling (Tsai et al 2013).…”

“…Aldosterone is able to upregulate the expression of both MR and AGTR1 (Schiffrin et al 1985, Zennaro et al 1996, Tsai et al 2013. In cardiomyocytes, aldosterone control of MR expression is dependent on MR coupled to AGTR1 signalling and downstream ERK and JNK activation, whereas AGTR1 expression is regulated by MR-independent transactivation of AGTR1 signalling (Tsai et al 2013). Furthermore, aldosterone activation of MR increases transcription of angiotensin-converting enzyme (ACE) mRNA in the aorta of rats treated with aldosterone (Hirono et al 2007) and in cultured rat aortic endothelial cells (Sugiyama et al 2005).…”

“…Local production of aldosterone is not involved, as angiotensin II-treated VSMCs do not express aldosterone synthase and gene expression is not altered by aldosterone synthase inhibition (Jaffe & Mendelsohn 2005). Conversely, MR acts via AGTR1 to upregulate profibrotic markers such as collagen 1A (COL1A) and 3A (COL3A) and α-smooth muscle actin (SMA) (Tsai et al 2013). Therefore, the MR and AGTR1 are intertwined at multiple points facilitating cooperation of different effector systems of RAAS with implications for both homeostasis and in disease states.…”

“…Transactivation of other receptor systems is involved in MR-mediated remodelling. AGTR1 transactivation is required for the upregulation of fibrotic and hypertrophic genes such as transforming growth factor-beta (TGF-β), Col1a, Col3a and Acta2 (which encodes α-smooth muscle actin) in cardiomyocytes via ERK and JNK (Tsai et al 2013), while the pro-hypertrophic MEF2 requires AGTR1 signalling via the G-protein coupled receptor kinase (GRK) 5 (Cannavo et al 2016).…”