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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

102 Citations (Web of Science)

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.

Result 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.

Conclusion/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
  • DIABETES-ASSOCIATED ATHEROSCLEROSIS
  • NADPH OXIDASE
  • ACCELERATED ATHEROSCLEROSIS
  • PHARMACOLOGICAL INHIBITION
  • OXIDATIVE STRESS
  • BLOOD-PRESSURE
  • KNOCKOUT MICE
  • MOUSE MODEL
  • KEY ROLE
  • RENOPROTECTION

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