Increased expression of the receptor for advanced glycation end-products in human peripheral neuropathies

Background: Diabetic neuropathy and idiopathic neuropathy are among the most prevalent neuropathies in human patients. The molecular mechanism underlying pathological changes observed in the affected nerve remains unclear but one candidate molecule, the receptor for advanced glycation end-products (RAGE), has recently gained attention as a potential contributor to neuropathy. Our previous studies revealed that RAGE expression is higher in porcine and murine diabetic nerve, contributing to the inflammatory mechanisms leading to diabetic neuropathy. Here, for the first time, we focused on the expression of RAGE in human peripheral nerve. Methods: Our study utilized de-identified human sural nerve surplus obtained from 5 non-neuropathic patients (control group), 6 patients with long-term mild-to-moderate diabetic neuropathy (diabetic group) and 5 patients with mild-to-moderate peripheral neuropathy of unknown etiology (idiopathic group). By using immunofluorescent staining and protein immunoblotting we studied the expression and colocalization patterns of RAGE and its ligands: carboxymethyllysine (CML), high mobility group box 1 (HMBG1) and mammalian Diaphanous 1 (mDia1) in control and neuropathic nerves. Results: We found that in a normal, healthy human nerve, RAGE is expressed in almost 30% of all nerve fibers and that number is higher in pathological states such as peripheral neuropathy. We established that the levels of RAGE and its pro-inflammatory ligands, CML and HMBG1, are higher in both idiopathic and diabetic nerve, while the expression of the RAGE cytoplasmic domain-binding partner, mDia1 is similar among control, diabetic, and idiopathic nerve. The highest number of double stained nerve fibers was noted for RAGE and CML: similar to 76% (control), similar to 91% (idiopathic) and similar to 82% (diabetic) respectively. Conclusions: Our data suggest roles for RAGE and its inflammatory ligands in human peripheral neuropathies and lay the foundation for further, more detailed and clinically oriented investigation involving these proteins and their roles in disorders of the human peripheral nerve.