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Diabetologia. 2017 May;60(5):927-937. doi: 10.1007/s00125-017-4215-5. Epub 2017 Feb 3.

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

Author information

1
Diabetic Complications Division, Baker IDI Heart & Diabetes Institute, PO Box 6492, St Kilda Rd, Melbourne, VIC, 8008, Australia. stephen.gray@bakeridi.edu.au.
2
Faculty of Medicine, Central Clinical School, Monash University, Melbourne, VIC, Australia. stephen.gray@bakeridi.edu.au.
3
Diabetic Complications Division, Baker IDI Heart & Diabetes Institute, PO Box 6492, St Kilda Rd, Melbourne, VIC, 8008, Australia.
4
Genkyotex SA, Geneva, Switzerland.
5
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
6
Department of Pharmacology, Faculty of Medicine, Health & Life Science, Maastricht University, Maastricht, the Netherlands.
7
Cardiovascular Research Institute Maastricht (CARIM), Faculty of Medicine, Health & Life Science, Maastricht University, Maastricht, the Netherlands.
8
Faculty of Medicine, Central Clinical School, Monash University, Melbourne, VIC, Australia.

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.

KEYWORDS:

Atherosclerosis; Diabetes; NADPH oxidase; Nephropathy; Oxidative stress

PMID:
28160092
DOI:
10.1007/s00125-017-4215-5
[Indexed for MEDLINE]

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