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Activation of Na+/H+‐exchanger‐1: a novel mechanism in diabetic neuropathy
Author(s) -
Obrosova Irina G.,
Ilnytska Olga,
Mashtalir Nazar,
Bai Fulu,
Yorek Mark A.,
Drel Viktor R.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1417-a
Enhanced Na + /H + ‐exchange (NHE) results in cytosol alkalinization and activation of the upper part of glycolysis which, under conditions of diabetes‐associated inhibition or insufficient upregulation of glyceraldehyde 3‐phosphate dehydrogenase, causes diversion of the glycolytic flux towards several pathways implicated in diabetic complications. We explored the role for Na + /H + ‐exchanger‐1 (NHE‐1), the most abundant NHE isoform, in DN. The specific NHE‐1 inhibitor, cariporide, prevented nerve blood flow (microelectrode polarography/hydrogen clearance) and sensory nerve conduction velocity (SNCV) deficits, and alleviated motor nerve conduction velocity (MNCV) deficit, thermal hyperalgesia (paw withdrawal and tail flick tests), mechanical hyperalgesia (von Frey anesthesiometer/rigid filament, and Randall‐Sellito tests) and tactile allodynia (flexible von Frey filaments) in STZ‐diabetic rats. MNCV deficit, thermal and mechanical hypoalgesia and tactile allodynia were less severe in NHE+/− than in NHE‐1+/+ STZ‐diabetic mice. High glucose‐induced NHE‐1 mRNA and protein overexpression (real‐time PCR and Western blotting) and NHE activation (BCECF fluorescence) were clearly manifest in human Schwann cells (HSC), and were mediated via poly (ADP‐ribose) polymerase‐1 (PARP‐1) and MAPK (ERK, SAPK/JNK)‐involved mechanisms. PARP‐1 activation and increased MAPK phosphorylation were detected within ~12–24 h of HSC exposure to 30 mM glucose. In conclusion, NHE‐1 activation is a novel fundamental mechanism in the pathogenesis of DN.