title: 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.
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Graduate School of Medicine, Ehime University, Tohon, Ehime, Japan. minchen@m.ehime-u.ac.jp
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Min
authors.forename: Masaki
authors.initials: M
authors.lastname: Mogi
authors.forename: Jun
authors.initials: J
authors.lastname: Iwanami
authors.forename: Akiko
authors.initials: A
authors.lastname: Sakata
authors.forename: Fei
authors.initials: F
authors.lastname: Jing
authors.forename: Kana
authors.initials: K
authors.lastname: Tsukuda
authors.forename: Kousei
authors.initials: K
authors.lastname: Ohshima
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Horiuchi
mesh_terms: D000450:Aldosterone / Q000633:toxicity*; D000804:Angiotensin II / Q000633:toxicity*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D004249:DNA Damage; D000077545:Eplerenone; D005727:Ganglia, Spinal / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D018161:Receptors, Mineralocorticoid / Q000502:physiology; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan
chemical_list: D044140:Receptor, Angiotensin, Type 1; D018161:Receptors, Mineralocorticoid; D013777:Tetrazoles; D000804:Angiotensin II; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone; D000068756:Valsartan; D014633:Valine