Abstract
The binding of renin or prorenin to the (pro)renin receptor (PRR) promotes angiotensin (Ang) II formation and mediates Ang II-independent signaling pathways. In the central nervous system (CNS), Ang II regulates blood pressure via inducing oxidative stress; however, the role of PRR-mediated Ang II-independent signaling pathways in oxidative stress in the CNS remains undefined. To address this question, Neuro-2A cells were infected with control virus or an adeno-associated virus encoding the human PRR. Human PRR over-expression alone increased ROS levels, NADPH oxidase activity, as well as NADPH oxidase (NOX) isoforms 2 and 4 mRNA expression levels and these effects were not blocked by losartan. Moreover, the increase in NOX 2 and NOX 4 mRNA levels, NADPH oxidase activity, and ROS levels induced by PRR over-expression was prevented by mitogen activated protein kinase/extracellular signal-regulated kinase 1 and 2 (MAPK/ERK1/2) inhibition, and phosphoinositide 3 kinase/Akt (IP3/Akt) inhibition, indicating that PRR regulates NOX activity and ROS formation in neuro-2A cells through Ang II-independent ERK1/2 and IP3/Akt activation. Interestingly, at a concentration of 2 nM or higher, prorenin promoted Ang II formation, and thus further increased the ROS levels in cultured Neuro-2A cells via PRR. In conclusion, human PRR over-expression induced ROS production through both angiotensin II-dependent and -independent mechanisms. We showed that PRR-mediated angiotensin II-independent ROS formation is associated with activation of the MAPK/ERK1/2 and PI3/Akt signaling pathways and up-regulation of mRNA level of NOX 2 and NOX4 isoforms in neuronal cells.
Highlights
It is well known that reactive oxygen species (ROS) play a pathophysiological role in the development of hypertension [1,2,3,4] and an activation of the renin-angiotensin system (RAS) is one of the key mediators in ROS production [5]
To dissect the molecular mechanisms of the increased brain PRR in the development of hypertension, we developed a new associated virus (AAV) coding for human PRR upstream of an eGFP reporter gene
AAV-hPRR-eGFP induced a significant increase in human PRR mRNA (Figure 1C, P,0.05) and protein levels (Figure 1D, E) in neuro-2A cells when compared with endogenous mouse PRR
Summary
It is well known that reactive oxygen species (ROS) play a pathophysiological role in the development of hypertension [1,2,3,4] and an activation of the renin-angiotensin system (RAS) is one of the key mediators in ROS production [5]. The binding of prorenin to PRR induces a conformational change of prorenin, conferring catalytic activity to prorenin, which leads to increased angiotensin II (Ang II) formation both in vitro and in vivo [7,8]. In addition to promoting Ang II formation and activating signals downstream, the binding of renin or prorenin to the PRR activates several Ang II-independent intracellular signaling pathways, increasing production of profibrotic and proinflammatory factors as well as cellular proliferation [11,12]. We hypothesized that the PRR mediates Ang II-dependent and -independent ROS formation in neuronal cells
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