Published in:
01-05-2017 | Article
Combined NOX1/4 inhibition with GKT137831 in mice provides dose-dependent reno- and atheroprotection even in established micro- and macrovascular disease
Published in: Diabetologia | Issue 5/2017
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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.
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.