THE ANGIOTENSIN-II TYPE-2 (AT(2)) RECEPTOR PROMOTES AXONAL REGENERATION IN THE OPTIC-NERVE OF ADULT RATS

The renin-angiotensin system (RAS) has been traditionally linked to bl ood pressure and volume regulation mediated. through the angiotensin I I (ANG II) type 1 (AT(1)) receptor. Here we report that ANG II via its ANG II type 2 (AT(2)) receptor promotes the axonal elongation of post natal rat retinal explants (postnatal day 11) and dorsal root ganglia neurons in vitro, and, moreover, axonal regeneration of retinal gangli on cells after optic nerve crush in vivo. In retinal explants, ANG II (10(-7)-10(-5) M) induced neurite elongation via its AT2 receptor, sin ce the effects were mimicked by die AT(2) receptor agonist CGP 42112 ( 10(-5) M) and were entirely abolished by costimulation with the AT, re ceptor antagonist PD 123177 (10(-5) M), but not by the AT, receptor an tagonist losartan (10(-5) M). To investigate whether ANG II is able to promote axonal regeneration in vivo, we performed optic nerve crush e xperiments in the adult rats. After ANG II treatment (0.6 nmol), an in creased number of growth-associated protein (GAP)-43-positive fibers w as detected and the regenerating fibers regularly crossed the lesion s ite (1.6 mm). Cotreatment with the AT(2) receptor antagonist PD 123177 (6 nmol), but not with the AT(1) receptor antagonist losartan (6 nmol ), completely abolished the ANG II-induced axonal regeneration, provid ing for the first time direct evidence for receptor-specific neurotrop hic action of ANG II in the central nervous system of adult mammals an d revealing a hitherto unknown function of the RAS.