Angiotensin II accelerates functional recovery in the rat sciatic nerve in vivo: role of the AT2 receptor and the transcription factor NF-kappaB

Abstract

The AT2 receptor regulates several functions of nerve cells, e.g., ionic fluxes, cell differentiation, and axonal regeneration, but also modulates programmed cell death. We tested the hypothesis that angiotensin II (ANG II) via its AT2 receptor not only promotes regeneration but also functional recovery after sciatic nerve crush in adult rats. ANG II (10(-7), 10(-9), 10(-11) M) applied locally via osmotic minipumps promoted functional recovery with maximal effects after the lowest concentration. The toe spread distance as a parameter for re-innervation after 20 days was significantly (P<0.01) greater (10.2+/-10.27 mm) compared with the control group (8.73+/-0.16 mm). The response to local electrical stimulation (return of sensorimotor function) was reduced to 14.6 days vs. 17.9 days in the control group (P<0.01). The AT2 receptor antagonist PD 123319 administered alone or in combination with ANG II completely prevented the ANG II-induced recovery, whereas the AT1 receptor antagonist losartan had no effect. Furthermore, ANG II induces, via the AT2 receptor, activation of the transcription factor NF-kappaB in Schwann cells. Histological criteria, morphometric analyses, and electron microscopy confirmed the functional data. These results are the first to present direct evidence for an involvement of the AT2 receptor and NF-kappaB in peripheral nerve regeneration.