Targeting the Extended Renin-Angiotensin System to Treat Traumatic Brain Injury
Abstract
Angiotensin II (Ang II), the vasoactive peptide of the classic renin-angiotensin system (RAS), serves many roles beyond blood pressure modulation. Activation of angiotensin II type I receptor (AT1R) by Ang II within the central nervous system can promote glial proliferation, local inflammation, and a decrease of cerebral blood flow. Angiotensin-(1-7) (Ang-(1-7)) is cleaved from Ang II by the actions of angiotensin converting enzyme 2 (ACE2) and is a ligand of the extended RAS. Ang-(1-7) has low affinity for AT1R instead acting as the ligand to the Mas receptor (MasR), which is widely expressed in the brain. The ACE2/Ang-(1-7)/MasR axis acts to counter Ang II signaling at many levels and has anti-inflammatory, vasodilatory, and neuroprotective effects. We are investigating novel therapeutics to improve recovery from traumatic brain injury (TBI), using a mouse model of controlled cortical impact (CCI). Our laboratory has previously shown that inhibition of AT1R signaling improves recovery from CCI injury in mice. Here we sought to determine if activation of Ang-(1-7)/MasR signaling would also be beneficial in this TBI model. Male adult C57BL/6 mice were injured by CCI. Ang-(1-7) or vehicle was administered by daily subcutaneous (SQ) injection or continuous SQ infusion, starting at 1 or 6 hours post injury until animals were sacrificed at 3 or 29 days post injury (dpi). Ang-(1-7) treatment attenuated motor deficits determined by the rotarod test at 3 dpi and improved cognitive recovery in the Morris water maze at 29 dpi. Brain histology and/or MRI indicated that Ang-(1-7) treated mice had a smaller lesion volume at 3, 10, 24, and 29 dpi. Pretreatment with the MasR antagonist A779 blocked Ang-(1-7)-reduced lesion volume at 3 dpi suggesting that this beneficial effect of Ang-(1-7) treatment was mediated through the MasR. Immunohistochemistry revealed that Ang-(1-7) treatment reduced microgliosis and astrogliosis and decreased neuronal and capillary loss at
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 11, 2018
- Accession Number
- AD1128414
Entities
People
- Zachary C. Janatpour
Organizations
- Uniformed Services University of the Health Sciences