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Combined NOX1/4 inhibition with GKT137831 in mice provides dose-dependent reno- and atheroprotection even in established micro- and macrovascular disease
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Combined NOX1/4 inhibition with GKT137831 in mice provides dose-dependent reno- and atheroprotection even in established micro- and macrovascular disease
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Combined NOX1/4 inhibition with GKT137831 in mice provides dose-dependent reno- and atheroprotection even in established micro- and macrovascular disease
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Journal Article
Combined NOX1/4 inhibition with GKT137831 in mice provides dose-dependent reno- and atheroprotection even in established micro- and macrovascular disease
2017
Overview
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.
Publisher
Springer Berlin Heidelberg,Springer Nature B.V
Subject
/ Atherosclerosis - metabolism
/ Atherosclerosis - prevention & control
/ Diabetes
/ Diabetes Complications - metabolism
/ Diabetes Complications - prevention & control
/ Diabetes Mellitus, Experimental - drug therapy
/ Diabetes Mellitus, Experimental - genetics
/ Diabetes Mellitus, Experimental - metabolism
/ Diabetic Nephropathies - metabolism
/ Diabetic Nephropathies - prevention & control
/ Medicine
/ Mice
/ NADH, NADPH Oxidoreductases - antagonists & inhibitors
/ NADH, NADPH Oxidoreductases - deficiency
/ NADH, NADPH Oxidoreductases - genetics
/ NADH, NADPH Oxidoreductases - metabolism
/ NADPH Oxidases - antagonists & inhibitors
