Journal
DIABETOLOGIA
Volume 60, Issue 5, Pages 927-937Publisher
SPRINGER
DOI: 10.1007/s00125-017-4215-5
Keywords
Atherosclerosis; Diabetes; NADPH oxidase; Nephropathy; Oxidative stress
Categories
Funding
- National Health & Medical Research Council (NHMRC) of Australia
- JDRF
- Diabetes Australia Research Trust
- Genkyotex SA research funding
- FP7 framework programme
- NHMRC Senior Research Fellowship
- MEC is a Senior Principal Research Fellow for the NHMRC
- JDRF Scholar
- Australian Diabetes Society Skip Martin Early Career Fellowship
- EU (Marie Curie International Reintegration Grant)
- Victorian Government's Operational Infrastructure Support Program
- European Research Council Advanced Grant [30983347E RADMED]
- British Heart Foundation [RG/13/7/30099] Funding Source: researchfish
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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.
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