Angiotensin-(1–7)-induced activation of ERK1/2 is cAMP/protein kinase A-dependent in glomerular mesangial cells

Abstract

The renin-angiotensin system (RAS) plays an important role in renal physiology and kidney injury. Although the cellular effects of the RAS activation are generally attributed to angiotensin II (ANG II), the recent identification of angiotensin-converting enzyme 2 has shifted the focus to other peptides including Ang-(1-7). The G protein-coupled receptor for Ang-(1-7), mas, is expressed by mesangial cells (MC) but the signal transduction pathways activated by Ang-(1-7) in MC have not been fully elucidated. Accordingly, we studied the effect of Ang-(1-7) on extracellular signal-related kinase (ERK)1/2 activation in rat MC. Ang-(1-7)-induced ERK1/2 phosphorylation in MC is time- and concentration-dependent. Pretreatment of MC with the mas receptor antagonist A-779 but not the AT(1) antagonist losartan or the AT(2) antagonist PD123319 abrogated ERK1/2 activation. Neither pretreatment with the NADPH oxidase inhibitors diphenyleneiodonium and apocynin nor pretreatment with the epidermal growth factor (EGF) receptor antagonists AG1478 and PD158780 attenuated Ang-(1-7)-induced activation of ERK1/2. Even though each of these compounds abolished ANG II-induced activation of ERK1/2. Ang-(1-7) increased intracellular cAMP levels and activated protein kinase A (PKA) and inhibition of either adenylyl cyclase or PKA activity attenuated Ang-(1-7)-induced ERK1/2 activation. In conclusion, Ang-(1-7)-induced activation of ERK1/2 is cAMP/PKA-dependent in MC, but independent of NADPH oxidase and the EGF receptor.

Angiotensin 1–7 mediates renoprotection against diabetic nephropathy by reducing oxidative stress, inflammation, and lipotoxicity

“…1C). We performed periodic acidSchiff (PAS) staining to assess the effect of ANG 1-7 treatment on mesangial expansion, a characteristic feature of diabetic nephropathy (26). PAS staining clearly showed that db/db mice had mesangial expansion, and ANG 1-7 treatment significantly reduced the size of the mesangium (Fig.…”

“…Angiotensin-converting enzyme 2 (ACE2), which cleaves ANG II into ANG 1-7, counterregulates the ACE/ANG II/AT1R axis (11,14,34,43,47). While genetic deletion of the Mas receptor leads to metabolic syndrome and renal injury (36), ANG 1-7 activates signaling pathways in mesangial (26) and proximal tubular cells (15) and attenuates diabetic nephropathy in Zucker diabetic fatty rats (17). Consequently, the ACE2/ANG 1-7/Mas receptor axis represents a promising therapeutic approach to the treatment of diabetic nephropathy.…”

G-Protein–Coupled Receptor MrgD Is a Receptor for Angiotensin-(1–7) Involving Adenylyl Cyclase, cAMP, and Phosphokinase A

“…We are the first group to establish cAMP as a readout for Ang-(1-7) receptor pharmacology, although there have been indications in the literature for such an association. Beside the work by Tallant and Clark 21 and by Liu et al 22 in primary cells, an article from 2012 showed indirect cAMP involvement in Ang-(1-7) signaling because its modulation of sympathetic activity in the paraventricular nucleus was abolished by an AC inhibitor and a PKA inhibitor. 31 Furthermore, physiological effects of the heptapeptide and effects in preclinical models also implicate the involvement of cAMP.…”

“…-(1-7). Furthermore, Liu et al 22 described the stimulation of intracellular signaling by Ang-(1-7) in glomerular MCs. Their data indicated that the heptapeptide can increase intracellular cAMP.…”

Angiotensin-converting enzyme 2, angiotensin-(1–7) and Mas: new players of the renin–angiotensin system

“…Interestingly, Liu et al (2012) recently reported that Ang-(1-7) induced ERK1/2 activation in glomerular mesangial cells via Mas. However, the authors demonstrated that, diverging from Ang II that induces ERK1/2 activation via NADPH oxidase activation or epidermal growth factor receptor (EGFR) transactivation, Ang-(1-7)/Mas leads to ERK1/2 phosphorylation in a cAMP/PKA-dependent manner (Liu et al 2012), suggesting that, in these cells, Mas is coupled to Gsa. Rakusan et al (2010) found that Mas deletion exacerbated renal hypertension in mice that was reversed with tempol or apocynin again suggesting a role in oxidative stress.…”