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Ralph Lucius^*, Stefan Gallinat^,, Philip Rosenstiel^*, Thomas Herdegen, Jobst Sievers^*, and Thomas Unger^,

From the ^* Institute of Anatomy and the Institute of Pharmacology, Christian-Albrechts-University Kiel, D-24105 Kiel, Germany; and the German Institute for High Blood Pressure Research, 69120 Heidelberg, Germany

The renin-angiotensin system (RAS) has been traditionally linked to blood pressure and volume regulation mediated through the angiotensin II (ANG II) type 1 (AT₁) receptor. Here we report that ANG II via its ANG II type 2 (AT₂) receptor promotes the axonal elongation of postnatal rat retinal explants (postnatal day 11) and dorsal root ganglia neurons in vitro, and, moreover, axonal regeneration of retinal ganglion cells after optic nerve crush in vivo. In retinal explants, ANG II (10^–7–10^–5 M) induced neurite elongation via its AT₂ receptor, since the effects were mimicked by the AT₂ receptor agonist CGP 42112 (10^–5 M) and were entirely abolished by costimulation with the AT₂ receptor antagonist PD 123177 (10^–5 M), but not by the AT₁ receptor antagonist losartan (10^–5 M). To investigate whether ANG II is able to promote axonal regeneration in vivo, we performed optic nerve crush experiments in the adult rats. After ANG II treatment (0.6 nmol), an increased number of growth-associated protein (GAP)-43–positive fibers was detected and the regenerating fibers regularly crossed the lesion site (1.6 mm). Cotreatment with the AT₂ receptor antagonist PD 123177 (6 nmol), but not with the AT₁ receptor antagonist losartan (6 nmol), completely abolished the ANG II–induced axonal regeneration, providing for the first time direct evidence for receptor-specific neurotrophic action of ANG II in the central nervous system of adult mammals and revealing a hitherto unknown function of the RAS.

Key Words: axonal regeneration • angiotensin receptor • PD 123177 • losartan • apoptosis

R. Lucius and S. Gallinat contributed equally to this work.

Abbreviations used: ANG, angiotensin; AT₁, ANG II type 1; AT₂, ANG II type 2; BDNF, brain-derived neurotrophic factor; CNS, central nervous system; DRG, dorsal root ganglia; GAP, growth-associated protein; GAPDH, glyceralaldehyde-3-phosphate dehydrogenase; GFAP, glial fibrillary acidic protein; RAS, renin–angiotensin system; RGC, retinal ganglion cell; RT-PCR, reverse transcriptase PCR.

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