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



GKT137831 was administered at two doses, 30 mg kg-1day-1and 60 mg kg-1day-1, to ApoE-/-mice 10 weeks after diabetes induction with streptozotocin (STZ), for a period of 10 weeks.



Consistent with Nox4-/-mouse data, GKT137831 was protective in a model of diabetic nephropathy at both the 30 mg kg-1day-1and 60 mg kg-1day-1doses, through suppression of proinflammatory and profibrotic processes. Conversely, in diabetic atherosclerosis, where Nox1-/yand 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-1day-1dose.



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.
Diabetic Complications Division, Baker IDI Heart & Diabetes Institute, PO Box 6492, St Kilda Rd, Melbourne, VIC, 8008, Australia. stephen.gray@bakeridi.edu.au.|Faculty of Medicine, Central Clinical School, Monash University, Melbourne, VIC, Australia. stephen.gray@bakeridi.edu.au.
Stephen P
SP
Gray
Diabetic Complications Division, Baker IDI Heart & Diabetes Institute, PO Box 6492, St Kilda Rd, Melbourne, VIC, 8008, Australia.
Jay C
JC
Jha
Diabetic Complications Division, Baker IDI Heart & Diabetes Institute, PO Box 6492, St Kilda Rd, Melbourne, VIC, 8008, Australia.
Kit
K
Kennedy
Diabetic Complications Division, Baker IDI Heart & Diabetes Institute, PO Box 6492, St Kilda Rd, Melbourne, VIC, 8008, Australia.
Erik
E
van Bommel
Diabetic Complications Division, Baker IDI Heart & Diabetes Institute, PO Box 6492, St Kilda Rd, Melbourne, VIC, 8008, Australia.
Phyllis
P
Chew
Genkyotex SA, Geneva, Switzerland.
Cedric
C
Szyndralewiez
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
Rhian M
RM
Touyz
Department of Pharmacology, Faculty of Medicine, Health & Life Science, Maastricht University, Maastricht, the Netherlands.|Cardiovascular Research Institute Maastricht (CARIM), Faculty of Medicine, Health & Life Science, Maastricht University, Maastricht, the Netherlands.
Harald H H W
HHHW
Schmidt
Diabetic Complications Division, Baker IDI Heart & Diabetes Institute, PO Box 6492, St Kilda Rd, Melbourne, VIC, 8008, Australia.|Faculty of Medicine, Central Clinical School, Monash University, Melbourne, VIC, Australia.
Mark E
ME
Cooper
Diabetic Complications Division, Baker IDI Heart & Diabetes Institute, PO Box 6492, St Kilda Rd, Melbourne, VIC, 8008, Australia.|Faculty of Medicine, Central Clinical School, Monash University, Melbourne, VIC, Australia.
Karin A M
KAM
Jandeleit-Dahm
D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism / Q000517:prevention & control; D048909:Diabetes Complications / Q000378:metabolism* / Q000517:prevention & control*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D011720:Pyrazoles / Q000627:therapeutic use*; D047069:Pyrazolones; D011725:Pyridines / Q000627:therapeutic use*; D011728:Pyridones
D011720:Pyrazoles; D047069:Pyrazolones; D011725:Pyridines; D011728:Pyridones; C576694:setanaxib; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C000614711:NOX1 protein, mouse; C422943:Nox4 protein, mouse
Atherosclerosis; Diabetes; NADPH oxidase; Nephropathy; Oxidative stress