Combined NOX1/4 inhibition with GKT137831 in mice provides dose-dependent reno- and atheroprotection even in established micro- and macrovascular disease

Stephen P. Gray, Jay C. Jha, Kit Kennedy, Erik van Bommel, Phyllis Chew, Cedric Szyndralewiez, Rhian M. Touyz, Harald H. H. W. Schmidt, Mark E. Cooper, Karin A. M. Jandeleit-Dahm

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51 Citations (Scopus)

Abstract

Aims/hypothesis: Oxidative stress is a promising target in diabetes-associated vasculopathies, with inhibitors of NADPH oxidases (NOX), in particular isoforms 1 and 4, shown to be safe in early clinical development. We have explored a highly relevant late-stage intervention protocol using the clinically most advanced compound, the NOX1/4 inhibitor GKT137831, to determine whether end-organ damage can be reversed/attenuated when GKT137831 is administered in the setting of established diabetic complications. Methods: GKT137831 was administered at two doses, 30 mg kg−1 day−1 and 60 mg kg−1 day−1, to ApoE−/− mice 10 weeks after diabetes induction with streptozotocin (STZ), for a period of 10 weeks. Results: Consistent with Nox4−/− mouse data, GKT137831 was protective in a model of diabetic nephropathy at both the 30 mg kg−1 day−1 and 60 mg kg−1 day−1 doses, through suppression of proinflammatory and profibrotic processes. Conversely, in diabetic atherosclerosis, where Nox1−/y and Nox4−/− mice have yielded qualitatively opposing results, the net effect of pharmacological NOX1/4 inhibition was protection, albeit to a lower extent and only at the lower 30 mg kg−1 day−1 dose. Conclusions/interpretation: As dose-dependent and tissue-specific effects of the dual NOX1/4 inhibitor GKT137831 were observed, it is critical to define in further studies the relative balance of inhibiting NOX4 vs NOX1 in the micro- and macrovasculature in diabetes.

Original languageEnglish
Pages (from-to)927-937
Number of pages11
JournalDiabetologia
Volume60
Issue number5
DOIs
Publication statusPublished - May 2017

Keywords

  • Atherosclerosis
  • Diabetes
  • NADPH oxidase
  • Nephropathy
  • Oxidative stress

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