Angiotensin II and aldosterone-induced neuronal damage in neurons through an astrocyte-dependent mechanism

Abstract

The contribution of the renin-angiotensin-aldosterone system (RAAS) to central nervous system (CNS) disorders is not yet fully understood. RAAS has been shown to be involved in the proliferation of astrocytes, which have a role in neuronal damage contributing to neurodegenerative diseases. However, the direct relationship between RAAS and neuronal damage is still unclear. We therefore examined the effect of angiotensin (Ang) II and aldosterone (Aldo) on damage to spinal ganglion neurons (SGNs) by regulating astrocytes. Ang II stimulation significantly increased DNA damage in SGNs in a time-dependent manner. This increase in DNA damage was further enhanced when SGNs were co-cultured with astrocytes. On the other hand, no significant increase was observed in SGNs co-cultured with astrocytes without Ang II stimulation. Moreover, the addition of conditioned medium from Ang II-treated astrocytes exacerbated SGN DNA damage. An Ang II type 1 receptor blocker, valsartan, inhibited Ang II-stimulated DNA damage but not DNA damage induced by conditioned medium prepared from astrocyte cultures. In contrast, an Aldo antagonist, eplerenone, significantly inhibited DNA damage induced by the culture medium from Ang II-treated astrocytes. Ang II-stimulated Aldo secretion in the conditioned medium from astrocytes. Furthermore, the administration of Aldo alone also enhanced DNA damage in SGNs. Finally, flow cytometric analysis showed that Ang II or Aldo treatment markedly increased the percentage of dead SGNs. In conclusion, Ang II-and Aldo-induced neuronal damage in SGNs through astrocytes regulation. Blocking Ang II and Aldo to target astrocytes might be useful for the treatment of CNS disorders.

Angiotensin II AT1 receptor blockers as treatments for inflammatory brain disorders

“…Astrocyte-dependent mechanisms contribute to sustain inflammation and participate in neuronal dysfunction and damage [41–43] (Figure 2). …”

“…Other parenchymal cells may participate in the central effects of AngII. Astrocytes contain significant numbers of AT 1 receptors [42,43] and these cells are the major source of angiotensinogen in the brain [82]. AT 1 receptors have been reported in cultured microglia [83,84], and ARBs are directly neuroprotective in microglia cell cultures [45,83].…”

Activation of mineralocorticoid receptors in the rostral ventrolateral medulla is involved in hypertensive mechanisms in stroke-prone spontaneously hypertensive rats

“…4,5 The beneficial effects of the MR antagonist spironolactone or the more specific antagonist eplerenone on end-organ damage have been studied in animal models. [6][7][8][9][10] It has been reported that MRs regulate epithelial Na channels (ENaCs) that are important for the regulation of sodium transport and the maintenance of extracellular fluid volume and arterial pressure (AP) in the kidney. 11 Recent studies have reported the distribution of MRs or ENaCs in the choroid plexus, ependyma and neurons, such as those in the supraoptic nucleus, paraventricular nucleus and nucleus tractus solitarius.…”

Ameliorative potential of angiotensin-converting enzyme inhibitor (ramipril) on chronic constriction injury of sciatic nerve induced neuropathic pain in mice

“…15,16 The RAAS modulators have been reported to ameliorate the neuropathic pain symptoms in various experimental animal models, i.e. aliskiren, a direct renin inhibitor; 17 , an angiotensin I receptor antagonist; 18 EMA401 and EMA300, an angiotensin II receptor antagonist; 19,20 and spironolactone, an aldosterone antagonist.…”