Spinal ADAM17 contributes to the pathogenesis of painful diabetic neuropathy in leptin receptor-deficient mice

Abstract

The pathogenesis of painful diabetic neuropathy (PDN) is complicated and remains not fully understood. A disintegrin and metalloprotease 17 (ADAM17) is an enzyme that is responsible for the degradation of membrane proteins. ADAM17 is known to be activated under diabetes, but its involvement in PDN is ill defined. Thus, we studied the role of spinal ADAM17 in PDN. Leptin receptor-deficient db/db mice were used as a mouse model of type 2 diabetes. To inhibit ADAM17, we used DNA-modified siRNA against ADAM17 (siADAM17) or TAPI-1, an ADAM17 inhibitor. The number of ADAM17-positive neurons was increased in the spinal dorsal horn (lamina I-V) in db/db mice, while ADAM17-positive microglia were increased only in lamina I-II. Inhibition of spinal ADAM17 by siADAM17 or TAPI-1 significantly attenuated PDN observed in db/db mice. Among several substrates of ADAM17, angiotensin (Ang)-converting enzyme 2 (ACE2) expression was significantly decreased in the spinal plasma membrane of db/db mice. Intrathecal administration of Ang (1–7), a peptide generated by ACE2, to db/db mice produced an anti-hyperalgesic effect, which was abolished by the MAS1 receptor antagonist A779. Our findings reveal a critical role for spinal ADAM17 in the pathogenesis of PDN mediated by the degradation of ACE2, and suggest a novel pain control mechanism acting through the degradation of plasma membrane proteins in the cause of pathological pain.