Preservation of kidney function with combined inhibition of NADPH oxidase and angiotensin-converting enzyme in diabetic nephropathy.
OBJECTIVE
Antihypertensive therapies such as angiotensin-converting enzyme-1 inhibitors (ACEi) slow the decline in renal function seen with diabetic nephropathy, although there is still progression ultimately to end-stage renal disease. The aim of this study was to determine if there were added renoprotective benefits seen by combining ACEi with blockade of NADPH oxidase.


METHODS
Sprague-Dawley diabetic and non-diabetic rats were randomized to receive intervention therapy with apocynin (15 mg/kg/day, weeks 16-32), apocynin + the ACEi ramipril (1 mg/kg/day, weeks 16-32), or ramipril alone (1 mg/kg).


RESULTS
All three treatments retarded the development of albuminuria in the diabetic rats. Apocynin conferred its benefit either as a monotherapy or in combination with ramipril without affecting blood pressure per se. Renal morphological injury was attenuated by all three treatment strategies. Diabetes was associated with increasing renal fibronectin and type IV collagen protein expression, with the combination regimen resulting in the highest decrease in extracellular matrix accumulation. All three treatments prevented the diabetes-associated increases in renal cytosolic superoxide generation as well as urinary isoprostanes. While renal TGF-beta1 activation was reduced by ramipril treatment but not by apocynin as a monotherapy, kidney cortical membranous VEGF was reduced by apocynin as monotherapy and dual therapy but not by ramipril alone.


CONCLUSIONS
Combination of NADPH oxidase blockade with ACE inhibitors is a promising regimen which warrants further investigation as a way to confer additional renoprotection in diabetes.
Thallas-Bonke
Vicki
V
JDRF Einstein Centre for Diabetes Complications, Diabetes Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, Vic., Australia. vicki.thallas@bakeridi.edu.au
Coughlan
Melinda T
MT
Bach
Leon A
LA
Cooper
Mark E
ME
Forbes
Josephine M
JM
D000098:Acetophenones / Q000494:pharmacology*; D000419:Albuminuria / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D017257:Ramipril / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000098:Acetophenones; D000806:Angiotensin-Converting Enzyme Inhibitors; D004791:Enzyme Inhibitors; C056165:acetovanillone; D019255:NADPH Oxidases; D007703:Peptidyl-Dipeptidase A; D017257:Ramipril